NK cells and their receptors

RBMOnline - Vol 16 No 2. 2008 173-191 Reproductive BioMedicine Online; www.rbmonline.com/Article/3091 on web 7 January 2008

Symposium: Current knowledge on natural killer cells, pregnancy and pre-eclampsia NK cells and their receptors Joan Riley received her PhD in immunology from Washington University, St Louis, Missouri, USA. She is currently an Instructor in the Department of Obstetrics and Gynecology at Washington University. Her research focuses on mechanisms of uterine NK cell activation during pregnancy.

Dr Joan Riley Wayne M Yokoyama1,3, Joan K Riley2 1 Howard Hughes Medical Institute, Rheumatology Division, Department of Medicine; 2Department of Obstetrics and Gynecology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110 USA 3 Correspondence: Tel: +1 314 3629075; Fax: +1 314 3629257; e-mail: [email protected]

Abstract Despite early reports that natural killer (NK) cells are non-specific or have non-major histocompatibility complex (MHC)restricted killing, it is now clear that NK cells express a panoply of receptors with defined specificity for ligands expressed on their cellular targets. The roles of these receptors in terms of physiological NK cell effector functions, such as cytotoxicity and cytokine production, are beginning to be unravelled. Inasmuch as NK cells accumulate in the uterus, an appreciation of NK cell receptor specificities and their physiological functions should provide valuable clues to the role of NK cells in the uterus and during pregnancy. Keywords: activation, inhibition, major histocompatibility complex, NK cell receptors, selective expression, uterus

General description and selective NK cell markers Natural killer (NK) cells were initially described because they spontaneously kill certain tumour targets (Herberman et al., 1975; Kiessling et al., 1975). Developmental studies have provided strong evidence that NK cells belong to the lymphocyte lineage (Yokoyama et al., 2004). NK cells express several markers typically associated with other cells (Rolink et al., 1996) that can confuse investigators, but NK cells most closely resemble T cells. NK cells are typically large lymphocytes containing azurophilic granules (Timonen et al., 1981), but the large granular lymphocyte (LGL) morphology can also be displayed by activated cytotoxic T lymphocytes (CTL) (Shortman et al., 1983). However, mature NK cells are clearly not T cells even though they may also share cell surface molecules and effector functions (Lanier et al., 1986c). A thymus is not required for NK cell development; NK cells are normal in athymic nude mice. NK cells do not express the T-cell receptor (TCR)/CD3 complex and do not rearrange TCR genes (Ritz et al., 1985; Lanier et al., 1986a), appearing to be normal in mice with defects in recombination, such as scid mutation or Rag1

or Rag2 deficiencies (Hackett et al., 1986a; Mombaerts et al., 1992; Shinkai et al., 1992). They do not display CD3 components on the cell surface (Phillips et al., 1992) except for CD3ζ, which is associated with FcγRIII (CD16) and other NK cell activation receptors (Anderson et al., 1989; Lanier et al., 1989a). Moreover, CD3ζ is not required for NK cell development, although it is required for T cell development (Liu et al., 1993). Conversely, NK cells are completely absent in mice lacking components of the interleukin (IL)-15 receptor (IL-15R), even though there are only partial defects in T cell subsets. Finally, NK cells do not require the presence of major histocompatibility complex (MHC) class I (MHC-I) molecules on their targets for lysis, in marked contrast to CD8+ MHC-I-restricted CTL. Rather, NK cells more efficiently kill targets lacking MHC-I expression. Thus, NK cells – are clearly distinguishable from T cells because NK cells are sIg , – TCR/CD3 lymphocytes that can mediate natural killing against targets that may lack MHC-I expression. In the absence of a defining NK cell receptor analogous to the TCR, investigators have relied on several surface markers

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley that are selectively expressed on NK cells to help elucidate their functions. For example, NK cells constitutively express components of the IL-2 receptor, i.e. IL-2Rβ and IL-2Rγ, but they do not normally express the heterotrimeric, high affinity IL-2R comprised of α (p55), β (p75) and γ (p64) chains (Taniguchi and Minami, 1993). Instead, NK cells express the IL-15Rα chain to form a high affinity complex with IL-2Rβγ (Giri et al., 1995; Tagaya et al., 1996). IL-15 is required for NK cell development and also has anti-apoptotic effects (DiSanto et al., 1995; Lodolce et al., 1998; Kennedy et al., 2000; Cooper et al., 2002). Interestingly, the IL-15Rα chain on a cell can present IL-15 in trans to NK cells that can respond through IL2/15Rβγ (Dubois et al., 2002). Recent studies suggest that this mechanism is involved in dendritic cell stimulation of NK cells (Lucas et al., 2007). Although anti-IL-15Rα antibodies are not widely available at this time, the constitutive expression of IL15R complex on NK cells has practical usefulness, since antiIL-2Rβ (CD122) is sometimes used to identify naive CD3– NK cells or deplete them in mice (Tanaka et al., 1993).

role on NK cells is not conserved. Regardless, human peripheral blood NK cells can be separated into two subsets, a CD56dim and a smaller subset of NK cells that expresses CD56 at higher levels (CD56bright) (Lanier et al., 1986b; Cooper et al., 2001). The CD56dim phenotype is associated with greater cytotoxicity, whereas the CD56bright cells show more cytokine production. The subpopulations also tend to express CD16 and other receptors involved in target recognition differentially.

Other markers have also proven to be useful for analysis of NK cells. The NK1.1 molecule is especially important as a serological marker on mouse NK cells in C57BL strains (Hackett et al., 1986b; Lanier et al., 1986c), and anti-NK1.1 [monoclonal antibody (mAb) PK136] administration has long been used to selectively deplete NK cells (Seaman et al., 1987). However, mAb PK136 recognizes an allelic determinant that is confined to C57BL/6, C57BL/10, and a few other strains (Koo and Peppard, 1984). Moreover, whereas NK1.1 is encoded by Nkrp1c in C57BL/6 mice (Ryan et al., 1992), mAb PK136 recognizes another NKRP1 family member, NKRP1B, in Swiss. NIH and SJL/J mice (Carlyle et al., 1999; Kung et al., 1999). Fortunately, there are now available NK1.1+ congenic strains, such as BALB.B6-Cmv1r (catalogued as C.B6-Klra8Cmv1–r/ UwaJ at The Jackson Laboratory, Bar Harbor, ME) in which the C57BL/6 allele of NK1.1 has been genetically bred onto the BALB/c background which otherwise lacks the NK1.1 epitope (Scalzo et al., 1995). Finally, whereas a subpopulation of T cells expresses NK1.1 (Bendelac et al., 1997), these so-called ‘NKT cells’ can be distinguished from conventional NK cells by expression of TCR/CD3 complex, i.e. NKT cells are CD3+.

Effector functions of peripheral NK cells

In NK1.1– mouse strains, other markers may be useful. The mAb DX5 recognizes the α2 integrin that is expressed on most NK1.1+ CD3– cells and a similar splenocyte subpopulation in NK1.1– strains, although the α2 integrin is not restricted to NK cells and is widely expressed on other leukocytes (Arase et al., 2001; Edelson et al., 2004). Historically, the glycolipid determinant asialo-GM1 is also useful, as it is expressed by most if not all murine NK cells and a subpopulation of T cells (Kasai et al., 1980; Young et al., 1980; Suttles et al., 1986). Regardless, in most recent studies, the anti-NK1.1 mAb PK136 has become the reagent of choice for NK cell depletion unless an NK1.1– mouse strain is used (Hackett et al., 1986b; Lanier et al., 1986c; Seaman et al., 1987).

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Human NK cells selectively express CD56 (Hercend et al., 1985; Lanier et al., 1986b, 1989b), a molecule derived from alternative splicing of the gene encoding neural cell adhesion molecule (NCAM) involved in nervous system development and cell–cell interactions (Cunningham et al., 1987; Rutishauser et al., 1988). Interestingly, mouse CD56 is not useful as an NK cell marker (Barclay et al., 1997), suggesting that its functional

Therefore, most investigators consider mouse peripheral NK cells to be typically NK1.1+ (in appropriate strains), FcγRIII+ (CD16, see below), CD122+, and CD3–. Human peripheral NK cells are generally CD56+ and CD3–. Note that these markers are generally related to cells having natural killing capacity, but the markers themselves are not required for target recognition. Nevertheless, these markers have helped shape current concepts of NK cell biology and their effector functions that led to the identification of receptors responsible for NK cell recognition of their targets, topics that will be considered next.

Like CTL, NK cells kill targets via exocytosis of preformed cytoplasmic granules that resemble secretory lysosomes and contain perforin and granzymes (Clark and Griffiths, 2003). When activated by a sensitive target, both types of cytotoxic lymphocytes polarize their granules and reposition the microtubule-organizing centre (MTOC) and Golgi apparatus towards the target (Kupfer et al., 1983; Lieberman, 2003). The granule membrane ultimately fuses with the plasma membrane and externalizes, releasing granule contents. Ca2+dependent polymerization of perforin results in ‘perforation’ of the target cell plasma membrane, leading to apoptosis induced by the granzymes. This exocytic process can be initiated by specific activation receptors for target cell ligands, and is blocked by inhibitory receptors (described in more detail below). Importantly, granule formation is affected by Lyst, the molecule defective in beige (bg) mice and in humans with Chediak−Higashi syndrome (Barbosa et al., 1996; Perou et al., 1996). Activated NK cells and CTL also induce perforin-independent target killing via TNF superfamily members, such as Fas (Henkart, 1994; Arase et al., 1995; Montel et al., 1995; Lee et al., 1996; Oshimi et al., 1996; Screpanti et al., 2001; Takeda et al., 2001). However, mice deficient in these molecules or their receptors may manifest significant alterations in lymphoid organogenesis and splenic architecture as well as NK cell number and function (Iizuka et al., 1999; Ware, 2005), such that the relative contributions of these pathways to NK cell function are incompletely understood. Moreover, NK cells from mice deficient in perforin, granzymes, or molecules involved in granule formation or exocytosis (Lyst, Rab27a) demonstrate profound defects in natural killing in vitro (Kagi et al., 1994; Pham and Ley, 1999; Revell et al., 2005). Similar defects have been found with NK cells derived from patients lacking these components (Klein et al., 1994). Thus, granule exocytosis appears to be the predominant mechanism for natural killing. NK cells also produce cytokines when exposed to NK-sensitive targets or cross-linking of activation receptors (see below). RBMOnline®

Symposium - NK cells and their receptors - WM Yokoyama & JK Riley These cytokines include interferon-γ (IFNγ), tumour necrosis factor-α (TNFα), and granulocyte−macrophage colony stimulating factor (GM-CSF) (Degliantoni et al., 1985; Anegon et al., 1988; Cuturi et al., 1989). They can also be similarly triggered to produce chemokines (Dorner et al., 2002). NK cells also produce similar cytokines in response to other cytokines, such as IL-12 (Tripp et al., 1993) and type I interferons (interferon α/β, IFNα/β) that are produced following in-vivo administration of poly-I:C and other TLR ligands. In immune responses, NK cell production of cytokines occurs relatively early and influences the subsequent adaptive immune response; their responses to cytokines are regulated by complex interacting pathways (Biron, 2001).

Effector functions of uterine NK cells The accumulation of uterine NK (uNK) cells at the maternal–fetal interface during early pregnancy suggested an important role for these lymphocytes during gestation. During a normal human pregnancy, the majority of uNK cells are of the CD56brightCD16– phenotype (Starkey et al., 1988; Nishikawa et al., 1991). Human uNK cells demonstrate low cytotoxic capacity yet they effectively secrete a number of cytokines, chemokines, and growth factors (King et al., 1989; Saito et al., 1993; Li et al., 2001b; MoffettKing, 2002; Koopman et al., 2003; Kopcow et al., 2005; Hanna et al., 2006; Lash et al., 2006). Further clues to the role of NK cells in the uterus and during pregnancy were provided by a series of landmark studies conducted using NK cell-deficient mouse models (Guimond et al., 1997, 1998; Ashkar and Croy, 1999, 2000; Greenwood et al., 2000). These studies demonstrated that while mice deficient in NK cells are fertile, the implantation sites display abnormalities. The transformation of uterine spiral arteries to large diameter high volume blood vessels was impaired in NK cell deficient mice, as was the decidualization of uterine stromal cells. IFNγ was identified as the critical cytokine that is required for restructuring the uterine blood supply and for supporting the decidualization process during murine pregnancy (Ashkar and Croy, 1999, 2001; Ashkar et al., 2000). In addition to IFNγ, human uNK cells have also been shown to secrete cytokines such as TNFα, leukaemia inhibitory factor (LIF), colony-stimulating factor 1 (CSF1) and GM-CSF, chemokines including IL-8 and interferon-inducible protein-10 (IP-10), and angiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and angiopoietin-2 (Ang-2) some of which are also expressed by murine uNK cells (Moffett-King, 2002; Croy et al., 2006; Manaster and Mandelboim, 2007). Recent data demonstrated that human uNK cells have the ability to regulate trophoblast invasion (Hiby et al., 2004; Hanna et al., 2006). Thus a growing body of evidence suggests that uNK cells help to facilitate the establishment of a successful pregnancy through positive effects on vascularization and placentation, effects that are presumably affected by uNK cell recognition of fetal tissues.

NK cell recognition of targets: NK cell receptors Following intense investigation in the last 2 decades, some principles are now evident with regard to the receptors RBMOnline®

responsible for target recognition and activation: (i) NK cell receptors are germline-encoded and the receptors are therefore not unique for each NK cell, i.e. they are not strictly ‘clonotypic’ as in clonotypic TCR; (ii) target recognition involves both inhibitory and activation receptors; (iii) individual NK cells usually express several different receptors of each functional type simultaneously; (iv) the receptors often have promiscuous and overlapping specificities; (v) NK cell receptors specifically bind MHC-I molecules, but they are functionally and structurally distinct from other receptors that bind MHC-I, such as the TCR and CD8; (vi) NK cell receptors involved in tumour recognition are similar to those involved in recognition of virus-infected cells; and (vii) target killing is dependent on an integration of signals received from inhibitory and activation receptors. With these basic guidelines in mind, we will next review the receptors involved in target recognition and describe other receptors on NK cells (Table 1).

MHC-specific inhibitory receptors NK cells clearly have a different relationship to target cell MHC-I molecules than MHC-I-restricted CTL. Kärre and colleagues discovered that MHC-I-deficient tumours remained susceptible to in-vivo rejection, apparently by NK cells (Kärre et al., 1986). Conversely, target cell expression of MHC-I molecules appeared to have a protective effect against NK cell-mediated lysis in vitro (Quillet et al., 1988). Studies of β2microglobulin (β2m)-deficient mice added substantial support to the MHC-I protective effect (Hoglund et al., 1991; Liao et al., 1991) and those results resembled hybrid resistance whereby NK cells in irradiated F1 hybrid mice reject parental BM transplants due to MHC-I effects (Yu et al., 1992). Thus, the target cell expression of certain MHC-I molecules was related to resistance to natural killing, whereas absence of MHC-I was associated with susceptibility to NK cells. Based on these findings, Kärre proposed that NK cells are equipped to detect the absence of ‘self’ epitopes (Kärre, 1985). This ‘missing self’ hypothesis suggests that NK cells survey tissues for expression of MHC-I molecules that are normally ubiquitously expressed and that chronically prevent NK cell activity. If MHC-I molecules are down-regulated or mutated, NK cells are able to lyse the target. Such MHC-I downregulation may be physiologically important. For example, several pathogens, especially viruses, possess mechanisms that prevent the normal expression of MHC-I molecules on infected cells, providing means to avoid MHC-I-restricted T cells (Tortorella et al., 2000). The host therefore is endowed with two components (T and NK cells) with opposing requirements for self-MHC-I expression that should eliminate pathologic processes that might otherwise evade immune responses by any alteration of MHC-I expression. The missing-self hypothesis created a framework for initial attempts to define NK cell recognition of their targets. NK cells express inhibitory receptors specific for MHC-I that fall into two structural types (Yokoyama, 1995). First described in mice (Karlhofer et al., 1992a), one type consists of C-type lectin-like, disulphide-linked dimeric receptors with type II transmembrane topology (extracellular carboxyl termini). These receptors are encoded in the NK gene complex (NKC).

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley Table 1. The panoply of receptors expressed by NK cellsa. Receptor H M

Inhibitory Other names (I) or activation (A)

Ligand

References

– Ly49A X I Ly49, Ly-49 H-2Dd, Dk, Dp Ly49C X I H-2Kb – Ly49G2 X I H-2Dd – KIR2DL1 X I CD158a, p58.1 HLA-Cw2, Cw4, - – Cw5, -Cw6 KIR2DL2 X I CD158b, p58.2 HLA-Cw1, -Cw3, - – Cw7, -Cw8 KIR3DL1 X I NKB1 HLA-Bw4 – KIR3DL2 X I p140 HLA-A – LILRB1 X I CD85, ILT2, HLA – LIR1 LILRB2 X I ILT4, LIR2 HLA – Castells et al., 2001 Lilrb4 X I gp49 αvβ3 integrin CD94/NKG2A X I Kp43 HLA-E – CD94/NKG2A X Qa-1 – LAIR-1 X I Ep-CAM?, collagen? Meyaard et al., 2001, 2003; Lebbink et al., 2006) Siglec-7 X P75, AIRM1 Carbohydrates Falco et al., 1999; Nicoll et al., 2003, Avril et al., 2004; Varki and Angata, 2006 Siglec-9 X Zhang et al., 2000; Varki and Angata, 2006) Siglec-11 X Varki and Angata 2006 Siglec-E X Varki and Angata 2006 FcγRIII X X A CD16 Fc of IgG – Ly49D X A Chinese hamster Hanke et al., 1999; Idris et al., 1999; Nakamura et al., 1999a,b; Mehta et al., 2001a; Furukawa et al., 2002 MHC-I, H2Dd Ly49H A m157 – KIR2DS1 A HLA-Cw7 Vales-Gomez et al., 1998a KIR2DS4 A HLA-Cw4 Katz et al., 2001 CD94/NKG2C X A HLA-E – CD94/NKG2C X A Qa-1 – NKG2D X A, co- MICA, MICB, – stimulation ULBPs, RAET1 NKG2D X A, co- H60, RAE1, MULT1 – stimulation Nkrp1c X A NK1.1 ? – Nkrp1d X I Clrb – Nkrp1f X A Clrg – NKRP1A X I LLT1 – 2B4 X X A,I CD48 – CD2 X X A CD48 – NTBA X X NTBA – CRACC X X CRACC – NKp46 X X A Influenza – haemagglutinin NKp44 X A ? – NKp30 X A ? – Klrg1 X I Cadherins – CEACAM1 X I CEA – CD226 X A DNAM-1 necl-5 (CD155, PVR), – nectin-2 (CD112) CD96 X A Tactile necl-5 – CRTAM X A necl-2 –

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a These are the major receptors discovered on NK cells in humans (H) and mice (M), listed in order of appearance in the text. References are included for some receptors that are less fully described in the text; for all others, please see corresponding text.

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley The second structural type consists of Ig-superfamily receptors with type I transmembrane orientation that are encoded in the leukocyte receptor complex (LRC), and were first described in humans. Whereas there are examples of both structural types of receptors expressed on mouse and human NK cells, the lectinlike receptors (Ly49 receptors) are the major MHC-specific inhibitory receptors in mice and the Ig-like receptors (killer Ig-like receptors, KIR) predominate in humans. Mouse Ly49 and human KIR appear to be analogous receptors that share the same function and are thus thought to be excellent examples of convergent evolution (Barten et al., 2001).

1998; Wang et al., 2002). Structural and mutational analyses indicate that the lectin-like domain of Ly49A interacts with a wedge-like site (‘site 2’) on H2Dd involving the undersurface of the peptide-binding cleft, consisting of α1, α2 and α3 domains of the heavy chain and β2m (Tormo et al., 1999; Matsumoto et al., 2001a; Wang et al., 2002; Mitsuki et al., 2004). These studies also provide a structural explanation for species-specific β2m requirements in functional studies (Michaelsson et al., 2001). Thus, Ly49A recognizes site 2 in the MHC molecule in terms of trans recognition between the NK cell receptor and target cell MHC-I molecule.

Regardless of structural type, the inhibitory receptors contain cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM) consisting of V/I/L/SxYxxL/V (single amino acid code where x is any amino acid) (Long, 1999). Ligand engagement leads to phosphorylation of the ITIM, presumably by Src family tyrosine kinases, that then recruits the intracellular tyrosine phosphatase, SHP (SH2-containing protein tyrosine phosphatase)-1 (also known as SHP; haematopoietic cell phosphatase, HCP; protein tyrosine phosphatase 1C, PTP1C; and protein-tyrosine phosphatase, non-receptor-type, 6, PTPN6). Although other phosphatases, such as SHP-2, and SHIP (SH2containing inositol polyphosphate 5-phosphatase) can also be recruited to phosphorylated ITIM, the predominant phosphatase recruited by the NK cell inhibitory receptors appears to be SHP1, leading to inhibition of NK cell activation.

Recent studies strongly suggest that Ly49 molecules also bind MHC in a cis interaction between receptor and ligand on the NK cell itself (Doucey et al., 2004; Kim et al., 2005). These findings help explain the observation that the presence of selfMHC ligands leads to ‘down-regulation’ of Ly49 expression on primary NK cells in MHC congenic mice (Karlhofer, 1994; Olsson et al., 1995; Held et al., 1996b). However, the physiologic importance of cis interactions is incompletely understood.

Mouse Ly49 The Ly49A receptor was the first inhibitory MHC-I-specific receptor to be described in molecular terms (Karlhofer, 1992a). Ly49A is a disulfide-linked homodimer (44 kDa subunits), type II membrane orientation and C-type lectin superfamily homology (Chan and Takei, 1989; Yokoyama et al., 1989). Previously termed Ly49, it is now appreciated that Ly49A (Klra1) belongs to a family of highly related molecules (Yokoyama et al., 1990, 1993; Wong et al., 1991; Smith et al., 1994) encoded in the NKC on mouse chromosome 6. Multiple lines of evidence indicate that Ly49A is an inhibitory receptor specific for MHC-I, particularly H2Dd (Karlhofer et al., 1992a,b, 1994; Correa et al., 1994; Daniels et al., 1994; Kane et al., 1994; Olsson et al., 1995; Held, 1996a,b; Nakamura et al., 1997; Hanke et al., 1999; Matsumoto et al., 2001a,b). Recognition of its MHC-I ligand results in inhibition of NK killing that is reversed with antibodies that disrupt the interaction. Recombinant Ly49A binds recombinant H2Dd with KD = ~2.0 µmol/l (Wang et al., 2002). Less extensive studies also indicate that Ly49A recognizes H2Dk and H2Dp (Karlhofer et al., 1992a, 1994; Hanke et al., 1999; Olsson-Alheim et al., 1999). Therefore, Ly49A is an MHC-I-specific receptor for H2Dd, H2Dk and H2Dp. The nature of the Ly49A interaction with MHC-I is fundamentally different from that of TCR with MHC-I because it is independent of the specific peptide bound by H2Dd (Correa and Raulet, 1995; Orihuela et al., 1996). However, bound peptides are required for appropriately folded MHC-I molecules to be recognized. Despite its structural homology to C-type lectins that are carbohydrate-binding proteins (Weis and Drickamer, 1996; Natarajan et al., 2002), Ly49A binding to its MHC ligands is not carbohydrate-dependent (Matsumoto et al., RBMOnline®

Other Ly49 receptors are also MHC-I-specific inhibitory receptors, although they have been less well studied than Ly49A. Genome sequence analysis now reveals 16 complete Ly49 genes in C57BL/6 mice (Wilhelm et al., 2002). Ly49C is the only known receptor specific for an H2b haplotype allele (H2Kb) in C57BL/6 mice (Brennan et al., 1994; Hanke et al., 1999; Kim et al., 2005). It is recognized by two mAbs: 5E6, which also binds Ly49I, and 4LO3311, which has exquisite specificity for Ly49C (Stoneman et al., 1995; Brennan et al., 1996). Ly49G2 (also known as LGL-1, recognized by mAb 4D11) binds H2Dd and conversely, H2Dd binds several different Ly49 receptors, indicating the overlapping and promiscuous specificities (Mason et al., 1995; Hanke et al., 1999). X-ray crystallographic studies indicated that Ly49C binds H2Kb in a manner similar to Ly49A interaction with H2Dd (Dam et al., 2003) but peptides bound to H2Kb can affect affinities (Dam et al., 2003) and functional interactions with Ly49C (Franksson et al., 1999). Thus, Ly49 receptors bind their MHC ligands in a structurally related manner. Individual NK cells may express multiple Ly49 receptors simultaneously (Brennan et al., 1996; Held et al., 1996b), often two or more Ly49s, suggesting that individual NK cells may be inhibited by more than one MHC-I molecule. While the total repertoire of Ly49 expression does not reach adult levels until sometime after 3 weeks of age (Dorfman and Raulet, 1998), the expression of Ly49 receptors is generally thought to be fixed and stable on an individual NK cell. Ly49 genes possess bidirectional, overlapping promoters directed in opposite orientations (Saleh et al., 2004). Transcription factors for gene transcription in one direction prevent binding of other factors for transcription in the opposite direction. A ‘probabilistic’ model was proposed to explain these findings that may also explain the stochastic expression of Ly49 genes and their stable expression (Raulet et al., 1997). The C57BL/6 alleles of the Ly49 receptors have been the most extensively studied thus far. However, the Ly49 receptors display extensive polymorphism (Yokoyama et al., 1990) with significant allelic polymorphism of the Ly49 cluster between inbred mouse strains with differences in gene number as well as

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley alleles for the Ly49 genes (Wilhelm et al., 2002; Proteau et al., 2004; Makrigiannis et al., 2005). These polymorphisms raise practical issues when studying NK cells because mAbs specific for one Ly49 allele may bind another molecule with a different function or specificity in another mouse strain (Makrigiannis et al., 2001; Mehta et al., 2001a,b).

Human killer immunoglobulin-like receptors (KIR) Originally identified with mAbs specific for receptors on human NK cells, the human Ig-like receptors with HLA specificity are now collectively known as killer Ig-like receptors (KIR) or CD158 (Moretta et al., 1990; Colonna et al., 1993, 1997; Litwin et al., 1994; Colonna and Samaridis, 1995; D’Andrea et al., 1995; Gumperz et al., 1995,;Wagtmann et al., 1995a; Long et al., 1996, 1997; Pende et al., 1996; Colonna, 1997; Moretta et al., 1997). The KIR nomenclature is based on whether the receptor has two or three Ig-like external domains (KIR2D or KIR3D respectively), and possession of a long (L) or short (S) cytoplasmic domain. In general, the L forms are inhibitory because they contain ITIM, whereas the S forms appear to be activation receptors (see below). Each distinct receptor is also designated by a number. The KIR2DL1 (CD158a, p58.1) molecule thus bears the original EB6 epitope and is specific for HLA-C (Asn77-Lys80) (HLA-Cw2, Cw4, -Cw5, -Cw6) whereas KIR2DL2 (CD158b, p58.2) has the GL183 epitope and is specific for HLA-C (Ser77-Asn80)(HLACw1, -Cw3, -Cw7, -Cw8). KIR3DL1, originally named NKB1, is specific for HLA-Bw4. KIR3DL2 was originally named p140 and has HLA-A specificity. There is abundant evidence that the KIR2DL and KIR3DL molecules are inhibitory HLA class I-specific receptors, including the binding of soluble receptors to HLA molecules (Wagtmann et al., 1995b; Dohring and Colonna, 1996; Fan et al., 1996; Cambiaggi et al., 1997). The KIR bind their HLA ligands with Kd = ~10 µmol/l (Vales-Gomez et al., 1998b; Maenaka et al., 1999; Boyington et al., 2000) and binding is affected by peptide that is bound by HLA molecules (Maenaka et al., 1999) and Zn2+ (Rajagopalan and Long, 1998; Vales-Gomez et al., 2001). Moreover, crystallographic studies of KIR2DL1 and KIR2DL2 complexed with their cognate HLA ligands indicate that they bind HLA class I molecules in a manner analogous to recognition of MHC by TCR (Boyington et al., 2000; Fan et al., 2001). KIR2DL1 interacts with Lys80 of HLA-Cw4 and KIR2DL2 contacts Asn80 of HLA-Cw3, accounting for the previously described HLA-C groupings and KIR specificities in functional studies (Colonna et al., 1993; Cella et al., 1994; Luque et al., 1996; Mandelboim et al., 1996, 1997; Colonna, 1997). However, neither KIR2DL molecule has extensive contacts with peptides bound to HLA-C (Rajagopalan et al., 1997). Thus, KIR and Ly49 bind their MHC ligands in markedly distinct ways, despite their analogous functions as MHC-specific inhibitory receptors.

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The KIR are encoded in the LRC on human chromosome 19q13.4 that encodes many other Ig-like receptors (Kelley et al., 2005) but the mouse LRC on chromosome 7qA1 does not include genes for KIR-like molecules. Instead mouse KIR-like molecules are encoded on the X chromosome (Hoelsbrekken et al., 2003; Welch et al., 2003). Like the mouse Ly49s, the human KIR display remarkable polymorphism and haplotype diversity divided into two major haplotypes (Bashirova et al., 2006) (see

http://www.ebi.ac.uk/ipd/kir/index.html). Several KIR genes have been termed framework loci because they appear to be present in all haplotypes described thus far. With such extensive polymorphism, a large number of different KIR genotypes have already been described that have provided clues to new receptors and ligand specificities, valuable links to the role of NK cells and their receptors in disease pathogenesis and tissue transplantation (reviewed in Bashirova et al., 2006), and more broadly, human evolution because the polymorphisms are distributed differently in the various ethnic populations.

Other human Ig-like receptors specific for MHC Also encoded in the LRC, just centromeric to the KIR genes, are the genes for the human LILR (leukocyte Ig-like receptor) family, which appear to be less polymorphic than the KIR genes (Wilson et al., 2000). There are two general forms of these receptors, those that appear to be activation receptors, and those with ITIM characteristic of inhibitory receptors. LILRB1 (CD85, ILT2 or LIR1) and LILRB2 (ILT4 or LIR2) have cytoplasmic ITIM and recognize HLA class I molecules (Colonna et al., 1997; Cosman et al., 1997; Banham et al., 1999). LILRB1 is broadly expressed whereas LILRB2 is not expressed on NK cells but is expressed by DCs and monocytes (Allan et al., 1999). A human CMV protein, UL18, binds LILRB1 with much higher affinity than HLA molecules, suggesting that LILRB1 plays a role in host defence (Chapman et al., 1999). LILRB1 has four Ig-like domains and binds the α3 domain of most, if not all, classical and non-classical HLA class I molecules (Chapman et al., 1999). The crystal structure of LILRB1 bound to HLA-A2 (3.4 Å resolution) reveals that it binds MHC molecules under the peptide-binding domain where it contacts α3 and β2m, more similar to Ly49 engagement of MHC than KIR (Willcox et al., 2003).

Human and mouse CD94/NKG2 CD94 and the NKG2 (excluding NKG2D) family of molecules are C-type lectin-like molecules encoded in the NKC (Houchins et al., 1991; Ho et al., 1998). CD94 has a short seven aminoacid cytoplasmic domain, suggesting that it cannot signal on its own (Chang et al., 1995) but it heterodimerizes with NKG2 molecules (Lazetic et al., 1996; Phillips et al., 1996; Carretero et al., 1997). While CD94 may be expressed as a homodimer, the NKG2 partner provides the signalling motif, whether inhibition (NKG2A, NKG2B is an alternatively spliced form of NKG2A) or activation (NKG2C, see below) (Lazetic et al., 1996; Houchins et al., 1997). The CD94/NKG2 receptors were initially thought to have promiscuous interactions with many classical (class Ia) and non-classical (class Ib) HLA molecules. However, CD94/NKG2 receptors directly recognize HLA-E (human) or Qa-1 (mouse) (Borrego et al., 1998; Braud et al., 1998; Lee et al., 1998). HLA-E and Qa-1 are MHC-Ib molecules that are widely expressed with limited polymorphism (Koller et al., 1988; Wei and Orr, 1990; Ulbrecht et al., 1992). Both are expressed with β2m and a peptide repertoire largely derived from the leader sequences of MHC-Ia molecules (Aldrich et al., 1994; Soloski et al., 1995; Salcedo et al., 1998; Vance et al., 1998). Their expression thus requires RBMOnline®

Symposium - NK cells and their receptors - WM Yokoyama & JK Riley normal production of HLA-E or Qa-1 and synthesis of certain MHC-Ia molecules. Thus, these studies indicate the conservation of the CD94/NKG2 receptor-HLA-E/Qa-1 ligand pair.

MHC-I specific inhibitory receptor expression in the uterus In contrast to conventional NK cells, uNK cells are exposed to a somewhat different MHC class I microenvironment. The trophectoderm cells of the implanted blastocyst differentiate into the invading trophoblast cells and eventually form the fetal portion of the placenta (Wang and Dey, 2006). In humans, the extravillous trophoblast (EVT) cells that invade the uterus have direct contact with the maternal immune system, as do other trophoblast subsets. As NK cell effector functions are tightly regulated by MHC-I molecules, the MHC expression pattern on EVT cells and MHC-I specific receptor expression in the uterus undoubtedly influence uNK function. In general, trophoblast cells in both humans and mice lack expression of MHC-II molecules and exhibit limited expression of MHC-I (Moffett and Loke, 2006). HLA-A and HLA-B are not expressed on human villous and EVT cells (Faulk and Temple, 1976; Goodfellow et al., 1976). EVT cells do, however, express HLA-C, which is a polymorphic class I molecule (King et al., 1996, 2000b). HLAC specific inhibitory receptors expressed on human uNK cells include KIR2DL2/3 and KIR2DL1 (Hiby et al., 1997; Verma et al., 1997; Chao et al., 1999; Koopman et al., 2003; Yamada et al., 2005). The expression pattern of murine inhibitory Ly49 receptors on uNK cells is less well defined. EVT cells also express HLA-G and HLA-E, which display limited polymorphism (Ellis et al., 1990; Chumbley et al., 1993; King et al., 2000a). The expression of HLA-G, a non-classical MHC-I molecule, has been of major interest to reproductive immunologists because of its selective expression on trophoblasts (Le Bouteiller et al., 1996). HLA-G expression is thought to be physiologically important for fetal–maternal tolerance, if HLA-G inhibits the maternal NK cells that accumulate at the site of implantation of the embryo that generally does not express MHC-I (Yokoyama, 1997). HLA-G expression can be detected by CD94/NKG2 receptors recognizing HLA-G leader sequences in the context of HLA-E (Soderstrom et al., 1997; Navarro et al., 1999). Moreover, ILT2 can directly recognize HLA-G (Colonna et al., 1997; Allan et al., 1999; Vitale et al., 1999). HLA-G can also be recognized by KIR2DL4, an unusual receptor because it contains only one ITIM, in contrast to the two ITIM in other KIR, and it contains a charged transmembrane residue (Cantoni et al., 1998; Ponte et al., 1999; Rajagopalan and Long, 1999). Nevertheless, KIR2DL4 binding inhibits NK cell activity. Although there are some discrepancies (summarized in Lanier et al., 1999), many receptors for HLA-G are expressed on human uNK cells (Ponte et al., 1999; King et al., 2000a, 2003; Kusumi et al., 2006), suggesting that they may be involved in maternal−fetal tolerance.

ITIM so their inhibitory function has been predicted if not directly tested. However, the ITIM is closely related to the immunoreceptor tyrosine-based activation motif (ITAM), and the immunoreceptor tyrosine-based switch motif (ITSM) that are involved in activation, so some caution is required because the motifs may also be involved in other signalling processes. Nonetheless, peripheral NK cells (and other leukocytes) express multiple MHC-independent inhibitory receptors, such as LAIR-1 and the Siglecs (Table 1); how they participate in responses of conventional and uNK cells are just beginning to be elucidated.

NK cell activation receptors The absence of MHC-I does not always result in killing, initially suggesting that NK cells express a second type of receptor for target cell ligands (Yokoyama, 1993; Yokoyama et al., 1993). In this two receptor model, the MHC-I inhibitory receptor controls the action of an activation receptor. In most circumstances, the inhibitory receptor effect dominates over the activation receptor, but it is possible to overcome inhibition by stronger activation receptor signalling. NK cells can be stimulated to mediate killing of IgG-coated targets through Fc binding by FcγRIII (CD16) receptor, i.e., antibody-dependent cellular cytotoxicity (ADCC). Moreover, anti-FcγRIII can also trigger through CD16, a process termed ‘redirected lysis’ or ‘reverse ADCC’ because the antibody binds in the opposite orientation to ADCC. Redirected lysis also occurs with antibodies against other putative receptors when IgG reacts specifically with the NK cell receptor and its Fc portion binds a target cell Fc receptor (FcγR) that apparently provides bridging and cross-linking effects (Leo et al., 1986). If FcγR binding on the target is prevented with FcγR-deficient targets, F(ab’)2 fragments of the anti-NK cell receptor antibody, or antitarget cell FcγR Ab blockade, NK cell triggering and target lysis do not occur. Many putative NK cell activation receptors were initially discovered with the redirected lysis assay.

Activation receptors related to the MHC-I-specific inhibitory receptors

MHC-independent NK cell inhibitory receptors

Many NK cell activation receptors are encoded in the NKC and LRC, and are distinguished from the inhibitory receptors by the absence of cytoplasmic ITIM. The activation receptors typically contain charged transmembrane residues that facilitate association with signalling chains having immunoreceptor tyrosine-based activation motifs (ITAM) analogous to ITAM in TCR and BCR complexes (D/ExxYxxL/Ix6–8YxxL/I). NK cells express three ITAM-containing signalling chains: CD3ζ, FcεRIγ, and DAP12 (DNAX associated protein of 12 kDa, also known as killer activating receptor associated protein, KARAP; Ly83; tyrosine kinase binding protein, Tyrobp). NK cells also express DAP10 that contains a YxxM motif for recruitment of phosphatidylinositol 3-kinase (PI3K) instead of an ITAM. The signalling chains generally provide two major functions to the activation receptors, i.e. cell surface expression as well as signal transduction.

As already mentioned, NK cells also express a growing list of inhibitory receptors for non-MHC ligands (Table 1) (Kumar and McNerney, 2005). Most of these receptors contain cytoplasmic

Murine Ly49D and Ly49H, for example, are related to the inhibitory Ly49 receptors for MHC-I, but do not contain cytoplasmic ITIM and have charged transmembrane residues

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley for association with DAP12 and activation (Mason et al., 1996; Smith et al., 1998; Bakker et al., 2000; Smith et al., 2000). Ly49D recognizes a Chinese hamster MHC-I molecule in an example of xenogeneic specificity (Idris et al., 1999; Nakamura et al., 1999b). Ly49H is responsible for genetic resistance of C57BL/6 mice to murine cytomegalovirus (CMV) (Scalzo et al., 1990; Brown et al., 2001; Daniels et al., 2001; Lee et al., 2001) because it recognizes m157, an MHC-I-like molecule encoded by the virus (Arase et al., 2002; Smith et al., 2002). Similarly, molecular cloning of human KIR led to identification of two (also known as p50) or three domain Ig-like receptors with short cytoplasmic domains lacking the ITIM, known as KIR2DS or KIR3DS, respectively (Moretta et al., 1995; Biassoni et al., 1996). The KIR2DS isoforms may be difficult to distinguish from the KIR2DL inhibitory receptors, because of cross-reactive mAbs. It is, however, thought that these activation receptors are also expressed on human uNK cells (Hiby et al., 1997; MoffettKing, 2002). As with the Ly49 activation receptors, there is some evidence that these killer cell activation receptors (KAR) may recognize HLA class I molecules, apparently with lower affinity than the corresponding inhibitory receptors (ValesGomez et al., 1998a, Katz et al., 2001). These data may help explain the dominance of inhibition over activation, but further studies are required. The NKG2 family contains members that associate with CD94 and activate NK cells (Houchins et al., 1991; Plougastel and Trowsdale, 1997). NKG2C and NKG2E lack cytoplasmic ITIM, and contain charged transmembrane residues for association with DAP12 (Lazetic et al., 1996; Wu et al., 2000). Like CD94/ NKG2A inhibitory receptors, these heterodimers recognize HLA-E or Qa-1 (Llano et al., 1998; Vance et al., 1999). The inhibitory form appears to bind with higher affinity to HLA-E than the activating form (Vales-Gomez et al., 1999) and there may be peptide preferences between the different functional forms (Kraft et al., 2000). Thus, perhaps unlike the activating and inhibitory forms of the Ly49s and KIR, the CD94/NKG2 receptors may discriminate between subtle differences in their MHC-Ib ligands.

FcγRIII (CD16) and ADCC The first molecularly defined activation receptor on NK cells was FcγRIII (CD16), through which NK cells mediate ADCC (Takai et al., 1994; Hazenbos et al., 1996). NK cells generally express only one of the known Fcγ receptors (Ravetch and Kinet, 1991), specifically the transmembrane isoform, termed FcγRIIIA in humans, whereas in mice only the transmembrane isoform (FcγRIII) is present (Perussia et al., 1989). On NK cells, FcγRIII molecules are physically associated with FcεRIγ homodimers, FcεRIγCD3ζ heterodimers, or γ−ζ heterodimers (Letourneur et al., 1991) that are required for optimal FcγRIII surface expression and signal transduction. Although ADCC is similar to natural killing, it is not required for NK cell target recognition (Lanier et al., 1988; Takai et al., 1994).

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The study of CD16 on NK cells was instructive in terms of the initial concept of activation receptors (Anegon et al., 1988), as described above. CD16 expression on NK cells also has practical implications because CD16-related artefacts must be considered when studying NK cells. Non-specific staining of NK cells in flow cytometry may occur if CD16 binding is

not taken into account. Finally, antibody blockade experiments should be done with caution if the antibody reacts with the target due to the possibility of ADCC.

NKG2D and ‘induced-self’ NKG2D (KLRK1) was first cloned from human NK cells as a cDNA related to NKG2A and C (Houchins et al., 1991). However, it is distinct from other NKG2 molecules because it has only limited sequence homology to other NKG2 molecules, and it does not heterodimerize with CD94. Instead, NKG2D is expressed as a disulphide-linked homodimer on both peripheral and uNK cells as well as differing T cell subsets in humans and mice (Bauer et al., 1999; Cerwenka et al., 2000; Diefenbach et al., 2000; Groh et al., 2003; Kopcow et al., 2005; Xie et al., 2005; Hanna et al., 2006; Vacca et al., 2006). Finally, NKG2D has functional properties and ligand specificities that differ from the other NKG2 molecules, indicating that NKG2D is not a member of the NKG2 family. In humans, NKG2D preferentially associates with DAP10 that contains a YxxM motif for recruitment of PI3K (Wu et al., 1999), consistent with initial functional studies suggesting that NKG2D acts as a co-stimulatory molecule on human T cells (Groh et al., 2001). Other studies have suggested that NKG2D can function as a primary activation receptor capable of triggering NK cells alone (Pende et al., 2001). Moreover, in mice but not humans, there are two alternatively spliced isoforms of NKG2D (Diefenbach et al., 2002; Gilfillan et al., 2002; Rosen et al., 2004) with the same extracellular domain but with differential requirements for association with DAP10 and DAP12. It is currently controversial as to whether or not the expression of the various isoforms is dependent on NK cell activation (Rabinovich et al., 2006). There are numerous ligands for NKG2D that are only distantly related to each other by sequence alignment (only ~20–25% amino acid identity), and mouse NKG2D can bind human ligands and vice versa. In humans, the ligands are MICA and MICB (MHC-I chain-related) and the ULBP (UL16 binding protein) family, also known as being encoded by the RAET1 gene family (official HUGO nomenclature) (Cosman et al., 2001; Kubin et al., 2001; Radosavljevic et al., 2002; Bacon et al., 2004). Mouse NKG2D recognizes H-60, the retinoic acid early inducible gene-1 (RAE-1) family, and murine ULBPlike transcript (MULT1) (Cerwenka et al., 2000; Diefenbach et al., 2000; Girardi et al., 2001; Carayannopoulos et al., 2002a). Interestingly, transcripts for members of the RAE-1 family have been detected in murine implantation sites (Xie et al., 2005). There are reciprocal strain-specific differences in ligand expression (Lodoen et al., 2003). The ligands display binding to NKG2D in two ways based on affinity (Li et al., 2001a; O’Callaghan et al., 2001; Carayannopoulos et al., 2002a,b), with affinities ranging from KD = ~300–1000 nmol/l to KD = 6–30 nmol/l. All studied NKG2D ligands have structural relatedness to MHC-I, although they do not associate with β2m or bind peptides (Li et al., 1999, 2001a; Radaev et al., 2001; McFarland et al., 2003). NKG2D binds its ligands in a manner that is more analogous to TCR docking on MHC and unlike Ly49 recognition, despite the relationship of NKG2D and Ly49 receptors as NKC-encoded, lectin-like homodimers that bind MHC-related molecules (Li et al., 2001a, 2002; Wolan et al., 2001).

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley NKG2D function has been described in terms of the ‘inducedself’ model because the expression of many of its ligands appears to be inducible such that they overcome inhibition through inhibitory MHC-I-specific receptors (Cerwenka et al., 2001; Diefenbach and Raulet, 2001a; Girardi et al., 2001; Regunathan et al., 2005). For example, expression of MICA and MICB is enhanced in inflammatory bowel disease (Groh et al., 1996). In mice, TLR signalling and DNA-damaging agents can induce NKG2D ligand expression (Hamerman et al., 2004; Gasser et al., 2005). Finally, evasion of NKG2D suggests its role in tumour surveillance and responses to infections (Cosman et al., 2001; Girardi et al., 2001; Groh et al., 2002; Krmpotic et al., 2002; Dunn et al., 2003; Lodoen et al., 2003, 2004; Welte et al., 2003; Wu et al., 2003; Hasan et al., 2005; Krmpotic et al., 2005; Smyth et al., 2005; Bui et al., 2006; Lenac et al., 2006), and NKG2D has been implicated in autoimmune diseases (Roberts et al., 2001; Groh et al., 2003; Hue et al., 2004; Meresse et al., 2004; Ogasawara et al., 2004). Thus, the function of NKG2D is generally thought to trigger immune cells due to inflammatory reactions, which lead to stress-induced expression of self-molecules (Diefenbach et al., 2001), resulting in immune control or autoimmunity.

et al., 1997), and DCAL-1 (Ryan et al., 2002), next to CD69 that are related to the mouse Clr family. Indeed, human NKRP1A binds LLT1, indicating that at least human LLT1 is a functional homologue of mouse Clr (Aldemir et al., 2005; Rosen et al., 2005). Thus, the Clr family consists of conserved molecules that are ligands for Nkrp1 receptors.

Nkrp1 and Clr: lectin-like receptors and ligands encoded by coupled genes in NKC

2B4 and related receptors

First identified on rat NK cells (Chambers et al., 1989), Nkrp1 molecules are also expressed by NKT cells (Bendelac et al., 1997). Nkrp1 (Klrb) is now known to belong to a family of lectin-like molecules with type II orientation encoded in the mouse and rat NKC (Giorda et al., 1991; Yokoyama et al., 1991; Plougastel et al., 2001b; Kveberg et al., 2006) but there is only a single gene (NKRP1A) in humans expressed on a NK cell subpopulation (Lanier et al., 1994). One member, Nkrp1c, is the NK1.1 marker (Ryan et al., 1992). Early studies indicated that rodent Nkrp1 molecules can activate NK cells in redirected lysis assays (Chambers et al., 1989; Karlhofer et al., 1991). Mouse Nkrp1c is functionally associated with FcεRIγ (Arase et al., 1997). Thus, Nkrp1 molecules were among the first described activation receptors on NK cells but as other families encoded in the NKC, there are also inhibitory Nkrp1 forms. Ligand specificities of the Nkrp1 molecules are just beginning to be understood. Nkrp1f recognizes C-type lectin related g (Clrg) (Zhou et al., 2001; Iizuka et al., 2003; Carlyle et al., 2004) and is a presumed activation receptor, since it has a charged transmembrane residue and no cytoplasmic signalling motifs. Nkrp1d is an inhibitory receptor expressed on all NK cells in C57BL/6 mice and is specific for Clrb. Thus, the Nkrp1 family is an MHC-independent system, representing the first examples of lectin-like receptor recognizing a lectin-like ligand, unlike MHC-like ligands for other NKC-encoded receptors. In turn, the Clr molecules belong to a small family with type II orientation and C-type lectin homology, also encoded in the NKC near Cd69 (Plougastel et al., 2001a). Transcript analysis indicates that Clrb is broadly expressed, whereas Clrg and Clrf genes are present in restricted and non-overlapping tissues, including NK cells. Genomic analyses indicate that there are three human genes, LLT1 (Boles et al., 1999), AICL (Hamann RBMOnline®

Interestingly, the Nkrp1 and Clr loci are co-localized in the NKC, from rodents to humans (Iizuka et al., 2003; Aldemir et al., 2005; Rosen et al., 2005; Carlyle et al., 2006; Kveberg et al., 2006; Plougastel et al., 2006). There is limited allelic polymorphism, with conservation of gene order and content, despite genetic proximity to the highly polymorphic Ly49 cluster (Iizuka et al., 2003; Carlyle et al., 2006), and genetic protection with suppression of recombination (Depatie et al., 1997; Forbes et al., 1997). These features resemble the tight genetic linkage of receptor and ligand genes and recombinational suppression of the self-incompatibility (SI) loci in plants to prevent selffertilization and related mating loci in other species (Ferris et al., 2002; Nasrallah, 2002). Taken together, these data, along with receptor−ligand specificity, suggest that the Nkrp1 and Clr molecules play a critical role in innate immune cell functions.

The 2B4 (CD244) molecule is a type I integral membrane protein belonging to a family of Ig-like molecules related to CD2 (Garni-Wagner et al., 1993; Tassi and Colonna, 2005; Veillette, 2006). Of these molecules, 2B4, CD2, NTBA (NK, T, and B cell antigen; also known as SLAMF6, or Ly108), and CD319 (CRACC, CD2-like receptor activating cytotoxic cells) are expressed on NK cells. In addition, 2B4 is also expressed on human uNK cells (Kopcow et al., 2005; Vacca et al., 2006). NTBA and CRACC are involved in homophilic interactions whereas 2B4 recognizes CD48, a GPI-linked molecule expressed on haematopoietic cells (Brown et al., 1998; Veillette, 2006). In turn, CD48 is also recognized by CD2. The cytoplasmic domains of 2B4, NTBA, and CRACC (and SLAM, CD84 and CD229) contain a motif with sequence similar to the ITIM, termed the ITSM consisting of TxYxxV/I consensus sequence (Shlapatska et al., 2001). The ITSM allow interactions with a signalling adapter, SLAM-associated protein (SAP, also known as SH2D1A) that is mutated in the X-linked lymphoproliferative syndrome (XLP), a human immunodeficiency involving abnormal proliferation of T and B cells during Epstein−Barr virus infections (Engel et al., 2003). The complexities of this receptor−ligand signalling pathway are still being unraveled because of differences in binding to different isoforms, different ligands, species differences, and potentially differential recruitment of SAP or its related molecules (reviewed in Veillette, 2006). Analysis of these discrepancies should be informative because 2B4 and related receptors demonstrate MHC-independent regulation of NK cells, and mediate inhibition in a functionally distinct manner from the MHC-specific inhibitory receptors; under certain circumstances, they can activate NK cells.

Natural cytotoxicity receptors (NCR) These receptors were first identified on human NK cells and consist of NKp46 (NCR1, CD335), NKp44 (NCR2, CD336), and NKp30 (NCR3, CD337) (Sivori et al., 1997; Pessino et

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley al., 1998; Vitale et al., 1998; Cantoni et al., 1999; Pende et al., 1999) with NKp44 being expressed only upon activation. NKp46 is encoded in the LRC, whereas NKp44 and NKp30 are encoded in the MHC (Neville and Campbell, 1999; Allcock et al., 2003). In the mouse, only the gene for NKp46 is present (Hollyoake et al., 2005). The NCR are type I integral proteins with one (NKp30, NKp44) or 2 (NKp46) Ig-like extracellular domains and contain charged transmembrane residues for association with ITAM-signalling chains, ζ−γ heterodimers for NKp46, NKp30 or DAP12 for NKp44. Human NKp46 appears to recognize influenza haemagglutinin on infected cells (Mandelboim et al., 2001). NKp46-deficient mice are susceptible to influenza, although this specificity is difficult to explain because the interaction is dependent on sialic acid residues on oligosaccharides on NKp46 itself and the ubiquitous expression of sialylated saccharides, (Gazit et al., 2006). NKp46 and the other NCR appear to play a role in cytotoxicity against tumours of varying origins because anti-NCR antibodies block target killing (Moretta et al., 2006), but no other ligands have been identified even though human NCR apparently recognize mouse tumours and vice versa; this suggests conservation of these receptor–ligand pairs across species (Moretta et al., 2006). Ligands for NKp30 and NKp44, while yet unidentified, are thought to be present at the maternal−fetal interface. HLA-G+ trophoblast cells showed specific binding to an NKp44 Fc fusion protein (Hanna et al., 2006). In addition, uterine decidual cells bound to both NKp30 and NKp44 Fc fusion proteins. Human uNK cells express all NCR (Kopcow et al., 2005, Hanna et al., 2006; Vacca et al., 2006). Thus, it is possible that uNK cells may become activated through at least one of these receptors.

Receptors for ligands on epithelial tissues

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NK cells display receptors for ligands that are expressed at cell−cell junctions in epithelial tissues, and thus are not normally exposed (Colonna, 2006). KLRG1 (also known as mast cell associated function antigen, MAFA) is a lectin-like receptor with cytoplasmic ITIM (Guthmann et al., 1995). Although expression of Klrg1 on NK cells is down-regulated in MHC-Ideficient mice, Klrg1 does not bind MHC (Corral et al., 2000). Instead, mouse Klrg1 binds E-, N-, and R-cadherin, leading to inhibition of NK cell lysis (Grundemann et al., 2006; Ito et al., 2006). Similarly, human CEACAM1 [carcinoembryonic antigen (CEA)-related adhesion molecule 1] contains a cytoplasmic ITIM and can directly bind CEA thereby potentially regulating NK cell activities in the decidua (Markel et al., 2002, 2004; Stern et al., 2005). On the other hand, human NK cells also express activation receptors for molecules at the adherens junction, i.e. they express CD226 (DNAM-1, DNAX accessory molecule-1), an LFA-1 associated receptor that recognizes necl-5 (nectin-like molecule-5, CD155, poliovirus receptor, PVR) and nectin-2 (CD112) (Shibuya et al., 1999). Human NK cells also express CD96 (tactile) that binds necl-5, and CRTAM (class I-restricted T cell-associated molecule), a receptor that recognizes necl-2 (Fuchs et al., 2004; Tahara-Hanaoka et al., 2004; Boles et al., 2005). Thus, these studies suggest that these receptors may affect different NK cell functions as related to epithelial tissues, such as transmigration across epithelium or attack against abnormal epithelial tissues that have disordered cell−cell junctions (reviewed in Colonna, 2006).

Conclusions A panoply of NK cell receptors is now amenable to analysis in the context of uNK cells in both humans and mice. As with the expression of HLA-G in fetal tissues, selective expression of NK cell receptors may help provide clues to further understanding the role of NK cells in reproduction.

Acknowledgements We thank members of our laboratories and our collaborators for their continued interest in dissecting the molecular basis for NK cell activities and tolerance. Investigations in the Yokoyama laboratory are supported by the National Institutes of Health, the Barnes-Jewish Hospital Research Foundation, and the Howard Hughes Medical Institute.

References Aldemir H, Prod’homme V, Dumaurier MJ et al. 2005 Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. Journal of Immunology 175, 7791–7795. Aldrich CJ, DeCloux A, Woods AS et al. 1994 Identification of a Tap-dependent leader peptide recognized by alloreactive T cells specific for a class Ib antigen. Cell 79, 649–658. Allan DS, Colonna M, Lanier LL et al. 1999 Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. Journal of Experimental Medicine 189, 1149–1156. Allcock RJ, Barrow AD, Forbes S et al. 2003 The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44. European Journal of Immunology 33, 567–577. Anderson P, Caligiuri M, Ritz J et al. 1989 CD3-negative natural killer cells express zeta TCR as part of a novel molecular complex. Nature 341, 159–162. Anegon I, Cuturi MC, Trinchieri G et al. 1988 Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells. Journal of Experimental Medicine 167, 452–472. Arase H, Mocarski ES, Campbell AE et al. 2002 Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326. Arase H, Saito T, Phillips JH et al. 2001 Cutting edge: the mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (alpha 2 integrin, very late antigen-2). Journal of Immunology 167, 1141–1144. Arase N, Arase H, Park SY et al. 1997 Association with FcR-g is essential for activation signal through NKR-P1 (CD161) in natural killer (NK) cells and NK1.1+ T cells. Journal of Experimental Medicine 186, 1957–1963. Arase H, Arase N, Saito T 1995 Fas-mediated cytotoxicity by freshly isolated natural killer cells. Journal of Experimental Medicine 181, 1235–1238. Ashkar AA, Croy BA 2001 Functions of uterine natural killer cells are mediated by interferon gamma production during murine pregnancy. Seminars in Immunology 13, 235–241. Ashkar AA, Croy BA 1999 Interferon-gamma contributes to the normalcy of murine pregnancy. Biology of Reproduction 61, 493–502. Ashkar AA, Di Santo JP, Croy BA 2000 Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. Journal of Experimental Medicine 192, 259–270. Avril T, Floyd H, Lopez F et al. 2004 The membrane-proximal immunoreceptor tyrosine-based inhibitory motif is critical for the

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley inhibitory signaling mediated by Siglecs-7 and -9, CD33-related Siglecs expressed on human monocytes and NK cells. Journal of Immunology 173, 6841–6849. Bacon L, Eagle RA, Meyer M et al. 2004 Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. Journal of Immunology 173, 1078–1084. Bakker AB, Hoek RM, Cerwenka A et al. 2000 DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353. Banham AH, Colonna M, Cella M et al. 1999 Identification of the CD85 antigen as ILT2, an inhibitory MHC class I receptor of the immunoglobulin superfamily. Journal of Leukocyte Biology 65, 841–845. Barbosa MD, Nguyen QA, Tchernev VT et al. 1996 Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 382, 262–265. Barclay AN, Brown MH, Law SKA et al. 1997 The Leucocyte Antigen Facts book, 2nd edn. Academic Press, San Diego. Barten R, Torkar M, Haude A et al. 2001 Divergent and convergent evolution of NK-cell receptors. Trends in Immunology 22, 52–57. Bashirova AA, Martin MP, McVicar DW et al. 2006 The killer immunoglobulin-like receptor gene cluster: tuning the genome for defense. Annual Review of Genomics and Human Genetics 7, 277–300. Bauer S, Groh V, Wu J et al. 1999 Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729. Bendelac A, Rivera MN, Park SH et al. 1997 Mouse CD1-specific NK1 T cells: development, specificity, and function. Annual Review of Immunology 15, 535–562. Biassoni R, Cantoni C, Falco M et al. 1996 The human leukocyte antigen (HLA)-C-specific ‘activatory’ or ‘inhibitory’ natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. Journal of Experimental Medicine 183, 645–650. Biron CA 2001 Interferons alpha and beta as immune regulators − a new look. Immunity 14, 661–664. Boles KS, Barchet W, Diacovo T et al. 2005 The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM. Blood 106, 779–786. Boles KS, Barten R, Kumaresan PR et al. 1999 Cloning of a new lectin-like receptor expressed on human NK cells. Immunogenetics 50, 1–7. Borrego F, Ulbrecht M, Weiss EH et al. 1998 Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. Journal of Experimental Medicine 187, 813–818. Boyington JC, Motyka SA, Schuck P et al. 2000 Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543. Braud VM, Allen DSJ, O’Callaghan CA et al. 1998 HLA-E binds to natural-killer-cell receptors CD94/NKG2A, B and C. Nature 391, 795–799. Brennan J, Lemieux S, Freeman JD et al. 1996 Heterogeneity among Ly-49C natural killer (NK) cells – characterization of highly related receptors with differing functions and expression patterns. Journal of Experimental Medicine 184, 2085–2090. Brennan J, Mager D, Jefferies W et al. 1994 Expression of different members of the Ly-49 gene family defines distinct natural killer cell subsets and cell adhesion properties. Journal of Experimental Medicine 180, 2287–2295. Brown MG, Dokun AO, Heusel JW et al. 2001 Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937. Brown MH, Boles K, Anton van der Merwe P et al. 1998 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. Journal of Experimental Medicine 188, 2083–2090. Bui JD, Carayannopoulos LN, Lanier LL et al. 2006 IFN-dependent down-regulation of the NKG2D ligand H60 on tumors. Journal of

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Immunology 176, 905–913. Cambiaggi A, Verthuy C, Naquet P et al. 1997 Natural killer cell acceptance of H-2 mismatch bone marrow grafts in transgenic mice expressing HLA-Cw3 specific killer cell inhibitory receptor. Proceedings of the National Academy of Sciences of the USA 94, 8088–8092. Cantoni C, Bottino C, Vitale M et al. 1999 NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily. Journal of Experimental Medicine 189, 787–796. Cantoni C, Verdiani S, Falco M et al. 1998 P49, a putative HLA class I-specific inhibitory NK receptor belonging to the immunoglobulin superfamily. European Journal of Immunology 28, 1980–1990. Carayannopoulos L, Naidenko O, Fremont D et al. 2002a Cutting edge: Murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D. Journal of Immunology 169, 4079–4083. Carayannopoulos LN, Naidenko OV, Kinder J et al. 2002b Ligands for murine NKG2D display heterogeneous binding behavior. European Journal of Immunology 32, 597–605. Carlyle JR, Mesci A, Ljutic B et al. 2006 Molecular and genetic basis for strain-dependent NK1.1 alloreactivity of mouse NK cells. Journal of Immunology 176, 7511–7524. Carlyle JR, Jamieson AM, Gasser S et al. 2004 Missing selfrecognition of Ocil/Clr-b by inhibitory NKR-P1 natural killer cell receptors. Proceedings of the National Academy of Sciences of the United States of America 101, 3527–3532. Carlyle JR, Martin A, Mehra A et al. 1999 Mouse NKR-P1B, a novel NK1.1 antigen with inhibitory function. Journal of Immunology 162, 5917–5923. Carretero M, Cantoni C, Bellon T et al. 1997 The CD94 and NKG2A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules. European Journal of Immunology 27, 563–567. Castells MC, Klickstein LB, Hassani K et al. 2001 gp49B1alpha(v)beta3 interaction inhibits antigen-induced mast cell activation. Nature Immunology 2, 436–442. Cella M, Longo A, Ferrara GB et al. 1994 NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80. Journal of Experimental Medicine 180, 1235–1242. Cerwenka A, Baron JL, Lanier LL 2001 Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proceedings of the National Academy of Sciences of the USA 98, 11521–11526. Cerwenka A, Bakker ABH, McClanahan T et al. 2000 Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12, 721–727. Chambers WH, Vujanovic NL, DeLeo AB et al. 1989 Monoclonal antibody to a triggering structure expressed on rat natural killer cells and adherent lymphokine-activated killer cells. Journal of Experimental Medicine 169, 1373–1389. Chan PY, Takei F 1989 Molecular cloning and characterization of a novel murine T cell surface antigen, YE1/48. Journal of Immunology 142, 1727–1736. Chang C, Rodriguez A, Carretero M et al. 1995 Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily. European Journal of Immunology 25, 2433–2437. Chao KH, Wu MY, Chen CD et al. 1999 The expression of killer cell inhibitory receptors on natural killer cells and activation status of CD4+ and CD8+ T cells in the decidua of normal and abnormal early pregnancies. Human Immunology 60, 791–797. Chapman TL, Heikeman AP, Bjorkman PJ 1999 The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603–613. Chumbley G, King A, Holmes N et al. 1993 In situ hybridization and northern blot demonstration of HLA-G mRNA in human trophoblast populations by locus-specific oligonucleotide. Human Immunology 37, 17–22.

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Clark R, Griffiths GM 2003 Lytic granules, secretory lysosomes and disease. Current Opinion in Immunology 15, 516–521. Colonna M 2006 Cytolytic responses: cadherins put out the fire. Journal of Experimental Medicine 203, 261–264. Colonna M 1997 Specificity and function of immunoglobulin superfamily NK cell inhibitory and stimulatory receptors. Immunological Reviews 155, 127–133. Colonna M, Samaridis J 1995 Cloning of immunoglobulinsuperfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 268, 367–368. Colonna M, Navarro F, Bellon T et al. 1997 A common inhibitory receptor for MHC class I molecules on human lymphoid and myelomonocytic cells. Journal of Experimental Medicine 186, 1809–1818. Colonna M, Borsellino G, Falco M et al. 1993 HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells. Proceedings of the National Academy of Sciences of the USA 90, 12000–12004. Cooper MA, Bush JE, Fehniger TA et al. 2002 In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 100, 3633–3638. Cooper MA, Fehniger TA, Caligiuri MA 2001 The biology of human natural killer-cell subsets. Trends in Immunology 22, 633–640. Corral L, Hanke T, Vance RE et al. 2000 NK cell expression of the killer cell lectin-like receptor G1 (KLRG1), the mouse homolog of MAFA, is modulated by MHC class I molecules. European Journal of Immunology 30, 920–930. Correa I, Raulet DH 1995 Binding of diverse peptides to MHC class I molecules inhibits target cell lysis by activated natural killer cells. Immunity 2, 61–71. Correa I, Corral L, Raulet DH 1994 Multiple natural killer cellactivating signals are inhibited by major histocompatibility complex class I expression in target cells. European Journal of Immunology 24, 1323–1331. Cosman D, Mullberg J, Sutherland CL et al. 2001 ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133. Cosman D, Fanger N, Borges L et al. 1997 A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 7, 273–282. Croy BA, van den Heuvel MJ, Borzychowski AM et al. 2006 Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones. Immunological Reviews 214, 161–185. Cunningham BA, Hemperly JJ, Murray BA et al. 1987 Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing. Science 236, 799–806. Cuturi MC, Anegon I, Sherman F et al. 1989 Production of hematopoietic colony stimulating factors by human natural killer cells. Journal of Experimental Medicine 169, 569–583. D’Andrea A, Chang C, Franz-Bacon K et al. 1995 Molecular cloning of NKB1. A natural killer cell receptor for HLA-B allotypes. Journal of Immunology 155, 2306–2310. Dam J, Guan R, Natarajan K et al. 2003 Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2K(b). Nature Immunology 4, 1213-1222. Daniels BF, Karlhofer FM, Seaman WE et al. 1994 A natural killer cell receptor specific for a major histocompatibility complex class I molecule. Journal of Experimental Medicine 180, 687–692. Daniels KA, Devora G, Lai WC et al. 2001 Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49h. Journal of Experimental Medicine 194, 29–44. Degliantoni G, Murphy M, Kobayashi M et al. 1985 Natural killer (NK) cell-derived hematopoietic colony-inhibiting activity and NK cytotoxic factor. Relationship with tumor necrosis factor and synergism with immune interferon. Journal of Experimental Medicine 162, 1512–1530. Depatie C, Muise E, Lepage P et al. 1997 High-resolution linkage map

in the proximity of the host resistance locus CMV1. Genomics 39, 154–163. Diefenbach A, Raulet DH 2001 Strategies for target cell recognition by natural killer cells. Immunological Reviews 181, 170–184. Diefenbach A, Tomasello E, Lucas M et al. 2002 Selective associations with signaling molecules determine stimulatory versus costimulatory activity of NKG2D. Nature Immunology 3, 1142–1149. Diefenbach A, Jensen ER, Jamieson AM et al. 2001 Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171. Diefenbach A, Jamieson AM, Liu SD et al. 2000 Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nature Immunology 1, 119–126. DiSanto JP, Muller W, Guy-Grand D et al. 1995 Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proceedings of the National Academy of Sciences of the USA 92, 377–381. Dohring C, Colonna M 1996 Human natural killer cell inhibitory receptors bind to HLA class I molecules. European Journal of Immunology 26, 365–369. Dorfman JR, Raulet DH 1998 Acquisition of Ly49 receptor expression by developing natural killer cells. Journal of Experimental Medicine 187, 609–618. Dorner BG, Scheffold A, Rolph MS et al. 2002 MIP-1alpha, MIP1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines. Proceedings of the National Academy of Sciences of the USA 99, 6181–6186. Doucey MA, Scarpellino L, Zimmer J et al. 2004 Cis association of Ly49A with MHC class I restricts natural killer cell inhibition. Nature Immunology 5, 328–336. Dubois S, Mariner J, Waldmann TA et al. 2002 IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells. Immunity 17, 537–547. Dunn C, Chalupny NJ, Sutherland CL et al. 2003 Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity. Journal of Experimental Medicine 197, 1427–1439. Edelson BT, Li Z, Pappan LK et al. 2004 Mast cell-mediated inflammatory responses require the alpha2 beta1 integrin. Blood 103, 2214–2220. Ellis SA, Palmer MS, McMichael AJ 1990 Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA class I molecule. Journal of Immunology 144, 731–735. Engel P, Eck MJ, Terhorst C 2003 The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nature Reviews Immunology 3, 813–821. Falco M, Biassoni R, Bottino C et al. 1999 Identification and molecular cloning of p75/AIRM1, a novel member of the sialoadhesin family that functions as an inhibitory receptor in human natural killer cells. Journal of Experimental Medicine 190, 793–802. Fan QR, Long EO, Wiley DC 2001 Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex. Nature Immunology 2, 452–460. Fan QR, Garboczi DN, Winter CC et al. 1996 Direct binding of a soluble natural killer cell inhibitory receptor to a soluble human leukocyte antigen-Cw4 class I major histocompatibility complex molecule. Proceedings of the National Academy of Sciences of the USA 93, 7178–7183. Faulk WP, Temple A 1976 Distribution of beta2 microglobulin and HLA in chorionic villi of human placentae. Nature 262, 799–802. Ferris PJ, Armbrust EV, Goodenough UW 2002 Genetic structure of the mating-type locus of Chlamydomonas reinhardtii. Genetics 160, 181–200. Forbes CA, Brown MG, Cho R et al. 1997 The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6. Genomics 41, 406–413. Franksson L, Sundback J, Achour A et al. 1999 Peptide dependency

RBMOnline®

Symposium - NK cells and their receptors - WM Yokoyama & JK Riley and selectivity of the NK cell inhibitory receptor Ly-49C. European Journal of Immunology 29, 2748–2758. Fuchs A, Cella M, Giurisato E et al. 2004 Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). Journal of Immunology 172, 3994–3998. Furukawa H, Iizuka K, Poursine-Laurent J et al. 2002 A ligand for the murine NK activation receptor Ly-49D: activation of tolerized NK cells from beta(2)-microglobulin-deficient mice. Journal of Immunology 169, 126–136. Garni-Wagner BA, Purohit A, Mathew PA et al. 1993 A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. Journal of Immunology 151, 60–70. Gasser S, Orsulic S, Brown EJ et al. 2005 The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190. Gazit R, Gruda R, Elboim M et al. 2006 Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nature Immunology 7, 517–523. Gilfillan S, Ho EL, Cella M et al. 2002 NKG2D recruits two distinct adapters to trigger natural killer cell activation and costimulation. Nature Immunology 3, 1150–1155. Giorda R, Trucco M 1991 Mouse NKR-P1. A family of genes selectively coexpressed in adherent lymphokine-activated killer cells. Journal of Immunology 147, 1701–1708. Girardi M, Oppenheim DE, Steele CR et al. 2001 Regulation of cutaneous malignancy by γδ T Cells. Science 294, 605–609. Giri JG, Kumaki S, Ahdieh M et al. 1995 Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO Journal 14, 3654–3663. Goodfellow PN, Barnstable CJ, Bodmer WF et al. 1976 Expression of HLA system antigens on placenta. Transplantation 22, 595–603. Greenwood JD, Minhas K, di Santo JP et al. 2000 Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta 21, 693–702. Groh V, Bruhl A, El-Gabalawy H et al. 2003 Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the USA 100, 9452–9457. Groh V, Wu J, Yee C et al. 2002 Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734–738. Groh V, Rhinehart R, Randolph-Habecker J et al. 2001 Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature Immunology 2, 255–260. Groh V, Bahram S, Bauer S et al. 1996 Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proceedings of the National Academy of Sciences of the USA 93, 12445–12450. Grundemann C, Bauer M, Schweier O et al. 2006 Cutting edge: Identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. Journal of Immunology 176, 1311–1315. Guimond MJ, Wang B, Croy BA 1998 Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice. Journal of Experimental Medicine 187, 217–223. Guimond MJ, Luross JA, Wang BP et al. 1997 Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TGE26 mice. Biology of Reproduction 56, 169–179. Gumperz JE, Litwin V, Phillips JH et al. 1995 The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor. Journal of Experimental Medicine 181, 1133–1144. Guthmann MD, Tal M, Pecht I 1995 A secretion inhibitory signal transduction molecule on mast cells is another C-type lectin. Proceedings of the National Academy of Sciences of the USA 92, 9397–9401. Hackett J, Jr., Bosma GC, Bosma MJ et al. 1986 Transplantable progenitors of natural killer cells are distinct from those of T and B

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lymphocytes. Proceedings of the National Academy of Sciences of the USA 83, 3427–3431. Hamann J, Montgomery KT, Lau S et al. 1997 AICL: a new activation-induced antigen encoded by the human NK gene complex. Immunogenetics 45, 295–300. Hamerman JA, Ogasawara K, Lanier LL 2004 Cutting edge: Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. Journal of Immunology 172, 2001–2005. Hanke T, Takizawa H, McMahon CW et al. 1999 Direct assessment of MHC class I binding by seven Ly49 inhibitory NK cell receptors. Immunity 11, 67–77. Hanna J, Goldman-Wohl D, Hamani Y et al. 2006 Decidual NK cells regulate key developmental processes at the human fetal−maternal interface. Nature Medicine 12, 1065–1074. Hasan M, Krmpotic A, Ruzsics Z et al. 2005 Selective downregulation of the NKG2D ligand H60 by mouse cytomegalovirus m155 glycoprotein. Journal of Virology 79, 2920–2930. Hazenbos WLW, Gessner JE, Hofhuis FMA et al. 1996 Impaired IgG-dependent anaphylaxis and arthus reaction in Fc-gamma-RIII (CD16) deficient mice. Immunity 5, 181–188. Held W, Cado D, Raulet DH 1996a Transgenic expression of the Ly49A natural killer cell receptor confers class I major histocompatibility complex (MHC)-specific inhibition and prevents bone marrow allograft rejection. Journal of Experimental Medicine 184, 2037–2041. Held W, Dorfman JR, Wu MF et al. 1996b Major histocompatibility complex class I dependent skewing of the natural killer cell LY49 receptor repertoire. European Journal of Immunology 26, 2286–2292. Henkart PA 1994 Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Immunity 1, 343–346. Herberman RB, Nunn ME, Lavrin DH 1975 Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity and specificity. International Journal of Cancer 16, 216–229. Hercend T, Griffin JD, Bensussan A et al. 1985 Generation of monoclonal antibodies to a human natural killer clone: Characterization of two natural killer associated antigens, NKH1A and NKH2, expressed on subsets of large granular lymphocytes. Journal of Clinical Investigation 75, 932–943. Hiby SE, Walker JJ, O’Shaughnessy K M et al. 2004 Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. Journal of Experimental Medicine 200, 957–965. Hiby SE, King A, Sharkey AM et al. 1997 Human uterine NK cells have a similar repertoire of killer inhibitory and activatory receptors to those found in blood, as demonstrated by RT-PCR and sequencing. Molecular Immunology 34, 419–430. Ho EL, Heusel JW, Brown MG et al. 1998 Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. Proceedings of the National Academy of Sciences of the USA 95, 6320–6325. Hoelsbrekken SE, Nylenna O, Saether PC et al. 2003 Cutting edge: molecular cloning of a killer cell Ig-like receptor in the mouse and rat. Journal of Immunology 170, 2259–2263. Hoglund P, Ohlen C, Carbone E et al. 1991 Recognition of b2microglobulin-negative b2m – T-cell blasts by natural killer cells from normal but not from b2m-mice: nonresponsiveness controlled by b2m – bone marrow in chimeric mice. Proceedings of the National Academy of Sciences of the USA 88, 10332–10336. Hollyoake M, Campbell RD, Aguado B 2005 NKp30 (NCR3) is a pseudogene in 12 inbred and wild mouse strains, but an expressed gene in Mus caroli. Molecular Biology and Evolution 22, 1661– 1672. Houchins JP, Lanier LL, Niemi EC et al. 1997 Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2C. Journal of Immunology 158, 3603–3609. Houchins JP, Yabe T, McSherry C et al. 1991 DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. Journal of Experimental Medicine 173, 1017–1020.

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Hue S, Mention JJ, Monteiro RC et al. 2004 A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367–377. Idris AH, Smith HRC, Mason LH et al. 1999 The natural killer cell complex genetic locus, Chok, encodes Ly49D, a target recognition receptor that activates natural killing. Proceedings of the National Academy of Sciences of the USA 96, 6330–6335. Iizuka K, Naidenko OV, Plougastel BF et al. 2003 Genetically linked C-type lectin-related ligands for the NKRP1 family of natural killer cell receptors. Nature Immunology 4, 801–807. Iizuka K, Chaplin DD, Wang Y et al. 1999 Requirement for membrane lymphotoxin in natural killer cell development. Proceedings of the National Academy of Sciences of the USA 96, 6336–6340. Ito M, Maruyama T, Saito N et al. 2006 Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. Journal of Experimental Medicine 203, 289–295. Kagi D, Ledermann B, Burki K et al. 1994 Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforindeficient mice. Nature 369, 31–37. Kane KP 1994 Ly-49 mediates EL4 lymphoma adhesion to isolated class I major histocompatibility complex molecules. Journal of Experimental Medicine 179, 1011–1015. Karlhofer FM, Hunziker R, Reichlin A et al. 1994 Host MHC class I molecules modulate in vivo expression of a NK cell receptor. Journal of Immunology 153, 2407–2416. Karlhofer FM, Ribaudo RK, Yokoyama WM 1992a MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells. Nature 358, 66–70. Karlhofer FM, Ribaudo RK, Yokoyama WM 1992b The interaction of Ly-49 with H-2Dd globally inactivates natural killer cell cytolytic activity. Transactions of the Association of American Physicians 105, 72–85. Karlhofer FM, Yokoyama WM 1991 Stimulation of murine natural killer (NK) cells by a monoclonal antibody specific for the NK1.1 antigen. IL-2-activated NK cells possess additional specific stimulation pathways. Journal of Immunology 146, 3662–3673. Kärre K 1985 Role of target histocompatibility antigens in regulation of natural killer activity: A reevaluation and a hypothesis. In: Herberman RB, Callewaert DM (eds) Mechanisms of Cytotoxicity by NK Cells, Academic Press, Orlando, pp. 81–103. Kärre K, Ljunggren H-G, Piontek G et al. 1986 Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–678. Kasai M, Iwamori M, Nagai Y et al. 1980 A glycolipid on the surface of mouse natural killer cells. European Journal of Immunology 10, 175–180. Katz G, Markel G, Mizrahi S et al. 2001 Recognition of HLA-Cw4 but not HLA-Cw6 by the NK cell receptor killer cell Ig-like receptor two-domain short tail number 4. Journal of Immunology 166, 7260–7267. Kelley J, Walter L, Trowsdale J 2005 Comparative genomics of natural killer cell receptor gene clusters. PLoS Genetics 1, 129– 139. Kennedy MK, Glaccum M, Brown SN et al. 2000 Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15deficient mice. Journal of Experimental Medicine 191, 771–780. Kiessling R, Klein E, Wigzell H 1975 Natural killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells: specificity and distribution according to genotype. European Journal of Immunology 5, 112–117. Kim S, Poursine-Laurent J, Truscott SM et al. 2005 Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713. King A, Allan DS, Bowen M et al. 2000a HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. European Journal of Immunology 30, 1623–1631. King A, Burrows TD, Hiby SE et al. 2000b Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta 21, 376–387. King A, Boocock C, Sharkey AM et al. 1996 Evidence for the

expression of HLA-C class I mRna and protein by human first trimester trophoblast. Journal of Immunology 156, 2068–2076. King A, Birkby C, Loke YW 1989 Early human decidual cells exhibit NK activity against the K562 cell line but not against first trimester trophoblast. Cellular Immunology 118, 337–344. Klein C, Philippe N, Le Deist F et al. 1994 Partial albinism with immunodeficiency (Griscelli syndrome). Journal of Pediatrics 125, 886–895. Koller BH, Geraghty DE, Shimizu Y et al. 1988 HLA-E. A novel HLA class I gene expressed in resting T lymphocytes. Journal of Immunology 141, 897–904. Koo GC, Peppard JR 1984 Establishment of monoclonal anti-NK-1.1 antibody. Hybridoma 3, 301–303. Koopman LA, Kopcow HD, Rybalov B et al. 2003 Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. Journal of Experimental Medicine 198, 1201–1212. Kopcow HD, Allan DS, Chen X et al. 2005 Human decidual NK cells form immature activating synapses and are not cytotoxic. Proceedings of the National Academy of Sciences of the USA 102, 15563–15568. Kraft JR, Vance RE, Pohl J et al. 2000 Analysis of Qa-1(b) peptide binding specificity and the capacity of CD94/NKG2A to discriminate between Qa-1-peptide complexes. Journal of Experimental Medicine 192, 613–624. Krmpotic A, Hasan M, Loewendorf A et al. 2005 NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145. Journal of Experimental Medicine 201, 211–220. Krmpotic A, Busch DH, Bubic I et al. 2002 MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo. Nature Immunology 3, 529–535. Kubin M, Cassiano L, Chalupny J et al. 2001 ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. European Journal of Immunology 31, 1428–1437. Kumar V, McNerney ME 2005 A new self: MHC-class-I-independent natural-killer-cell self-tolerance. Nature Reviews Immunology 5, 363–374. Kung SK, Su RC, Shannon J et al. 1999 The NKR-P1B gene product is an inhibitory receptor on SJL/J NK cells. Journal of Immunology 162, 5876–5887. Kupfer A, Dennert G, Singer SJ 1983 Polarization of the Golgi apparatus and the microtubule-organizing center within cloned natural killer cells bound to their targets. Proceedings of the National Academy of Sciences of the USA 80, 7224–7228. Kusumi M, Yamashita T, Fujii T et al. 2006 Expression patterns of lectin-like natural killer receptors, inhibitory CD94/NKG2A, and activating CD94/NKG2C on decidual CD56bright natural killer cells differ from those on peripheral CD56dim natural killer cells. Journal of Reproductive Immunology 70, 33–42. Kveberg L, Back CJ, Dai KZ et al. 2006 The novel inhibitory NKR-P1C receptor and Ly49s3 identify two complementary, functionally distinct NK cell subsets in rats. Journal of Immunology 176, 4133–4140. Lanier LL 1999 Natural killer cells fertile with receptors for HLA-G? Proceedings of the National Academy of Sciences of the USA 96, 5343–5345. Lanier LL, Chang C, Phillips JH 1994 Human NKR-P1A. A disulfidelinked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. Journal of Immunology 153, 2417–2428. Lanier LL, Cwirla S, Yu G et al. 1989a Membrane anchoring of a human IgG Fc receptor (CD16) determined by a single amino acid. Science 246, 1611–1613. Lanier LL, Testi R, Bindl J et al. 1989b Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. Journal of Experimental Medicine 169, 2233–2238. Lanier LL, Ruitenberg JJ, Phillips JH 1988 Functional and biochemical analysis of CD16 antigen on natural killer cells and granulocytes. Journal of Immunology 136, 3478–3485.

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley Lanier LL, Cwirla S, Federspiel N et al. 1986a Human natural killer cells isolated from peripheral blood do not rearrange T cell receptor b chain genes. Journal of Experimental Medicine 163, 209–214. Lanier LL, Le AM, Civin CI et al. 1986b The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. Journal of Immunology 136, 4480–4486. Lanier LL, Phillips JH, Hackett J Jr et al. 1986c Natural killer cells: definition of a cell type rather than a function. Journal of Immunology 137, 2735–2739. Lash GE, Schiessl B, Kirkley M et al. 2006 Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. Journal of Leukocyte Biology 80, 572–580. Lazetic S, Chang C, Houchins JP et al. 1996 Human natural killer cell receptors involved in MHC class I recognition are disulfidelinked heterodimers of CD94 and NKG2 subunits. Journal of Immunology 157, 4741–4745. Le Bouteiller P, Rodriguez AM, Mallet V et al. 1996 Placental expression of HLA class I genes. American Journal of Reproductive Immunology 35, 216–225. Lebbink RJ, de Ruiter T, Adelmeijer J et al. 2006 Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1. Journal of Experimental Medicine 203, 1419–1425. Lee N, Llano M, Carretero M et al. 1998 HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proceedings of the National Academy of Sciences of the USA 95, 5199–5204. Lee RK, Spielman J, Zhao DY et al. 1996 Perforin, Fas ligand, and tumor necrosis factor are the major cytotoxic molecules used by lymphokine-activated killer cells. Journal of Immunology 157, 1919–1925. Lee SH, Girard S, Macina D et al. 2001 Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nature Genetics 28, 42–45. Lenac T, Budt M, Arapovic J et al. 2006 The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60. Journal of Experimental Medicine 203, 1843–1850. Leo O, Sachs DH, Samelson LE et al. 1986 Identification of monoclonal antibodies specific for the T cell receptor complex by Fc receptor-mediated CTL lysis. Journal of Immunology 137, 3874–3880. Letourneur O, Kennedy IC, Brini AT et al. 1991 Characterization of the family of dimers associated with Fc receptors (Fc epsilon RI and Fc gamma RIII). Journal of Immunology 147, 2652–2656. Li P, McDermott G, Strong RK 2002 Crystal structures of RAE-1beta and its complex with the activating immunoreceptor NKG2D. Immunity 16, 77–86. Li P, Morris DL, Willcox BE et al. 2001 Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nature Immunology 2, 443–451. Li P, Willie ST, Bauer S et al. 1999 Crystal structure of the MHC class I homolog MIC-A, a gammadelta T cell ligand. Immunity 10, 577–584. Li XF, Charnock-Jones DS, Zhang E et al. 2001 Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells. Journal of Clinical Endocrinology and Metabolism 86, 1823– 1834. Liao NS, Bix M, Zijlstra M et al. 1991 MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253, 199–202. Lieberman J 2003 The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nature Reviews Immunology 3, 361–370. Litwin V, Gumperz J, Parham P et al. 1994 NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. Journal of Experimental Medicine 180, 537–543. Liu CP, Ueda R, She J et al. 1993 Abnormal T cell development in CD3-zeta-/- mutant mice and identification of a novel T cell population in the intestine. EMBO Journal 12, 4863–4875. Llano M, Lee N, Navarro F et al. 1998 HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2

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receptors: preferential response to an HLA-G-derived nonamer. European Journal of Immunology 28, 2854–2863. Lodoen MB, Abenes G, Umamoto S et al. 2004 The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60–NKG2D interactions. Journal of Experimental Medicine 200, 1075–1081. Lodoen M, Ogasawara K, Hamerman JA et al. 2003 NKG2Dmediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. Journal of Experimental Medicine 197, 1245– 1253. Lodolce JP, Boone DL, Chai S et al. 1998 IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676. Long EO 1999 Regulation of immune responses through inhibitory receptors. Annual Review of Immunology 17, 875–904. Long EO, Burshtyn DN, Clark WP et al. 1997 Killer cell inhibitory receptors–diversity, specificity, and function. Immunological Reviews 155, 135–144. Long EO, Colonna M, Lanier LL 1996 Inhibitory MHC class I receptors on NK and T cells: a standard nomenclature. Immunology Today 17, 100. Lucas M, Schachterle W, Oberle K et al. 2007 Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26, 503–517. Luque I, Solana R, Galiani MD et al. 1996 Threonine 80 on HLA-B27 confers protection against lysis by a group of natural killer clones. European Journal of Immunology 26, 1974–1977. Maenaka K, Juji T, Nakayama T et al. 1999 Killer cell immunoglobulin receptors and T cell receptors bind peptide-major histocompatibility complex class I with distinct thermodynamic and kinetic properties. Journal of Biological Chemistry 274, 28329–28334. Makrigiannis AP, Patel D, Goulet ML et al. 2005 Direct sequence comparison of two divergent class I MHC natural killer cell receptor haplotypes. Genes and Immunity 6, 71–83. Makrigiannis AP, Pau AT, Saleh A et al. 2001 Class I MHCbinding characteristics of the 129/J Ly49 repertoire. Journal of Immunology 166, 5034–5043. Manaster I, Mandelboim O 2007 The unique properties of human NK cells in the uterine mucosa. Placenta. doi:10.1016/ j.placenta.2007.10.006. Mandelboim O, Lieberman N, Lev M et al. 2001 Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055–1060. Mandelboim O, Reyburn HT, Sheu EG et al. 1997 The binding site of NK receptors on HLA-C molecules. Immunity 6, 341–350. Mandelboim O, Reyburn HT, Valesgomez M et al. 1996 Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules. Journal of Experimental Medicine 184, 913–922. Markel G, Mussaffi H, Ling KL et al. 2004 The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients. Blood 103, 1770–1778. Markel G, Wolf D, Hanna J et al. 2002 Pivotal role of CEACAM1 protein in the inhibition of activated decidual lymphocyte functions. Journal of Clinical Investigation 110, 943–953. Mason LH, Anderson SK, Yokoyama WM et al. 1996 The Ly49D receptor activates murine natural killer cells. Journal of Experimental Medicine 184, 2119-2128. Mason LH, Ortaldo JR, Young HA et al. 1995 Cloning and functional characteristics of murine large granular lymphocyte-1: a member of the Ly-49 gene family (Ly-49G2). Journal of Experimental Medicine 182, 293–303. Matsumoto N, Mitsuki M, Tajima K et al. 2001a The functional binding site for the C-type lectin-like natural killer cell receptor Ly49A spans three domains of its major histocompatibility complex class I ligand. Journal of Experimental Medicine 193, 147–158.

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Matsumoto N, Yokoyama WM, Kojima S et al. 2001b The NK cell MHC class I receptor Ly49A detects mutations on H-2Dd inside and outside of the peptide binding groove. Journal of Immunology 166, 4422–4428. Matsumoto N, Ribaudo RK, Abastado J-P et al. 1998 The lectin-like NK cell receptor Ly-49A recognizes a carbohydrate-independent epitope on its MHC class I ligand. Immunity 8, 245–254. McFarland BJ, Kortemme T, Yu SF et al. 2003 Symmetry recognizing asymmetry: analysis of the interactions between the C-type lectinlike immunoreceptor NKG2D and MHC class I-like ligands. Structure (Cambridge) 11, 411–422. Mehta IK, Smith HRC, Wang J et al. 2001a A ‘chimeric’ C57Lderived Ly49 inhibitory receptor resembling the Ly49D activation receptor. Cellular Immunology 209, 29–41. Mehta IK, Wang J, Roland J et al. 2001b Ly49A allelic variation and MHC class I specificity. Immunogenetics 53, 572–583. Meresse B, Chen Z, Ciszewski C et al. 2004 Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357–366. Meyaard L, van der Vuurst de Vries AR, de Ruiter T et al. 2003 Retraction. Journal of Experimental Medicine 198, 1129. Meyaard L, van der Vuurst de Vries AR, de Ruiter T et al. 2001 The epithelial cellular adhesion molecule (Ep-CAM) is a ligand for the leukocyte-associated immunoglobulin-like receptor (LAIR). Journal of Experimental Medicine 194, 107–112. Michaelsson J, Achour A, Rolle A et al. 2001 MHC Class I Recognition by NK receptors in the Ly49 family is strongly influenced by the beta(2)-microglobulin subunit. Journal of Immunology 166, 7327–7334. Mitsuki M, Matsumoto N, Yamamoto K 2004 A species-specific determinant on beta2-microglobulin required for Ly49A recognition of its MHC class I ligand. International Immunology 16, 197–204. Moffett A, Loke C 2006 Immunology of placentation in eutherian mammals. Nature Reviews Immunology 6, 584–594. Moffett-King A 2002 Natural killer cells and pregnancy. Nature Reviews Immunology 2, 656–663. Mombaerts P, Iacomini J, Johnson RS et al. 1992 RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877. Montel AH, Bochan MR, Hobbs JA et al. 1995 Fas involvement in cytotoxicity mediated by human NK cells. Cellular Immunology 166, 236–246. Moretta A, Biassoni R, Bottino C et al. 1997 Major histocompatibility complex class I-specific receptors on human natural killer and T lymphocytes. Immunological Reviews 155, 105–117. Moretta A, Sivori S, Vitale M et al. 1995 Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. Journal of Experimental Medicine 182, 875–884. Moretta A, Tambussi G, Bottino C et al. 1990 A novel surface antigen expressed by a subset of human CD3– CD16+ natural killer cells. Role in cell activation and regulation of cytolytic function. Journal of Experimental Medicine 171, 695–714. Moretta L, Bottino C, Pende D et al. 2006 Surface NK receptors and their ligands on tumor cells. Seminars in Immunology 18, 151–158. Nakamura MC, Linnemeyer PA, Niemi EC et al. 1999a Mouse Ly-49D recognizes H-2Dd and activates natural killer cell cytotoxicity. Journal of Experimental Medicine 189, 493–500. Nakamura MC, Naper C, Niemi EC et al. 1999b Natural killing of xenogeneic cells mediated by the mouse Ly-49D receptor. Journal of Immunology 163, 4694–4700. Nakamura MC, Niemi EC, Fisher MJ et al. 1997 Mouse Ly-49A interrupts early signaling events in natural killer cell cytotoxicity and functionally associates with the Shp-1 tyrosine phosphatase. Journal of Experimental Medicine 185, 673–684. Nasrallah JB 2002 Recognition and rejection of self in plant reproduction. Science 296, 305–308. Natarajan K, Dimasi N, Wang J et al. 2002 Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annual Review of Immunology 20,

853–885. Navarro F, Llano M, Bellon T et al. 1999 The ILT2(LIR1) and CD94/ NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. European Journal of Immunology 29, 277–283. Neville MJ, Campbell RD 1999 A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. Journal of Immunology 162, 4745–4754. Nicoll G, Avril T, Lock K et al. 2003 Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7dependent and -independent mechanisms. European Journal of Immunology 33, 1642–1648. Nishikawa K, Saito S, Morii T et al. 1991 Accumulation of CD16CD56+ natural killer cells with high affinity interleukin 2 receptors in human early pregnancy decidua. International Immunology 3, 743–750. O’Callaghan CA, Cerwenka A, Willcox BE et al. 2001 Molecular competition for NKG2D: H60 and RAE1 compete unequally for NKG2D with dominance of H60. Immunity 15, 201–211. Ogasawara K, Hamerman JA, Ehrlich LR et al. 2004 NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 20, 757–767. Olsson MY, Karre K, Sentman CL 1995 Altered phenotype and function of natural killer cells expressing the major histocompatibility complex receptor Ly-49 in mice transgenic for its ligand. Proceedings of the National Academy of Sciences of the USA 92, 1649–1653. Olsson-Alheim MY, Sundback J, Karre K et al. 1999 The MHC class I molecule H-2Dp inhibits murine NK cells via the inhibitory receptor Ly49A. Journal of Immunology 162, 7010–7014. Orihuela M, Margulies DH, Yokoyama WM 1996 The natural killer cell receptor Ly-49A recognizes a peptide-induced conformational determinant on its major histocompatibility complex class I ligand. Proceedings of the National Academy of Sciences of the USA 93, 11792–11797. Oshimi Y, Oda S, Honda Y et al. 1996 Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells. Journal of Immunology 157, 2909–2915. Pende D, Cantoni C, Rivera P et al. 2001 Role of NKG2D in tumor cell lysis mediated by human NK cells: co-operation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. European Journal of Immunology 31, 1076–1086. Pende D, Parolini S, Pessino A et al. 1999 Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. Journal of Experimental Medicine 190, 1505–1516. Pende D, Biassoni R, Cantoni C et al. 1996 The natural killer cell receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer. Journal of Experimental Medicine 184, 505–518. Perou CM, Moore KJ, Nagle DL et al. 1996 Identification of the murine beige gene by YAC complementation and positional cloning. Nature Genetics 13, 303–308. Perussia B, Tutt MM, Qiu WQ et al. 1989 Murine natural killer cells express functional Fc gamma receptor II encoded by the Fc gamma R alpha gene. Journal of Experimental Medicine 170, 73–86. Pessino A, Sivori S, Bottino C et al. 1998 Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. Journal of Experimental Medicine 188, 953–960. Pham CT, Ley TJ 1999 Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proceedings of the National Academy of Sciences of the USA 96, 8627–8632. Phillips JH, Chang CW, Mattson J et al. 1996 CD94 and a novel associated protein (94ap) form a NK cell receptor involved in the recognition of HLA-A, HLA-B, and HLA-C allotypes. Immunity

RBMOnline®

Symposium - NK cells and their receptors - WM Yokoyama & JK Riley 5, 163–172. Phillips JH, Hori T, Nagler A et al. 1992 Ontogeny of human natural killer (NK) cells: fetal NK cells mediate cytolytic function and express cytoplasmic CD3 epsilon,delta proteins. Journal of Experimental Medicine 175, 1055–1066. Plougastel B, Trowsdale J 1997 Cloning of NKG2-F, a new member of the NKG2 family of human natural killer cell receptor genes. European Journal of Immunology 27, 2835–2839. Plougastel BF, Yokoyama WM 2006 Extending missing-self? Functional interactions between lectin-like NKrp1 receptors on NK cells with lectin-like ligands. Current Topics in Microbiology and Immunology 298, 77–89. Plougastel B, Dubbelde C, Yokoyama WM 2001a Cloning of Clr, a new family of lectin-like genes localized between mouse Nkrp1a and CD69 genes. Immunogenetics 53, 209–214. Plougastel B, Matsumoto K, Dubbelde C et al. 2001b Analysis of a 1-Mb BAC contig overlapping the mouse Nkrp1 cluster of genes: cloning of three new Nkrp1 members, Nkrp1d, Nkrp1e, and Nkrp1f. Immunogenetics 53, 592–598. Ponte M, Cantoni C, Biassoni R et al. 1999 Inhibitory receptors sensing HLA-G1 molecules in pregnancy: decidua-associated natural killer cells express LIR-1 and CD94/NKG2A and acquire p49, an HLA-G1-specific receptor. Proceedings of the National Academy of Sciences of the USA 96, 5674–5679. Proteau MF, Rousselle E, Makrigiannis AP 2004 Mapping of the BALB/c Ly49 cluster defines a minimal natural killer cell receptor gene repertoire. Genomics 84, 669–677. Quillet A, Presse F, Marchiol-Fournigault C et al. 1988 Increased resistance to non-MHC-restricted cytotoxicity related to HLA A,B expression. Direct demonstration using beta 2-microglobulintransfected Daudi cells. Journal of Immunology 141, 17–20. Rabinovich B, Li J, Wolfson M et al. 2006 NKG2D splice variants: a reexamination of adaptor molecule associations. Immunogenetics 58, 81–88. Radaev S, Rostro B, Brooks AG et al. 2001 Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3. Immunity 15, 1039–1049. Radosavljevic M, Cuillerier B, Wilson MJ et al. 2002 A cluster of ten novel MHC class I related genes on human chromosome 6q24.2– q25.3. Genomics 79, 114–123. Rajagopalan S, Long EO 1999 A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. Journal of Experimental Medicine 189, 1093–1100. Rajagopalan S, Long EO 1998 Zinc bound to the killer cell-inhibitory receptor modulates the negative signal in human NK cells. Journal of Immunology 161, 1299–1305. Rajagopalan S, Long EO 1997 The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity. Journal of Experimental Medicine 185, 1523–1528. Raulet DH, Held W, Correa I et al. 1997 Specificity, tolerance and developmental regulation of natural killer cells defined by expression of class I-specific Ly49 receptors. Immunological Reviews 155, 41–52. Ravetch JV, Kinet JP 1991 Fc receptors. Annual Review of Immunology 9, 457–491. Regunathan J, Chen Y, Wang D, et al. 2005 NKG2D receptormediated NK cell function is regulated by inhibitory Ly49 receptors. Blood 105, 233–240. Revell PA, Grossman WJ, Thomas DA et al. 2005 Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions. Journal of Immunology 174, 2124–2131. Ritz J, Campen TJ, Schmidt RE et al. 1985 Analysis of T-cell receptor gene rearrangement and expression in human natural killer clones. Science 228, 1540–1543. Roberts AI, Lee L, Schwarz E et al. 2001 Cutting edge: NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. Journal of Immunology 167, 5527–5530. Rolink A, ten Boekel E, Melchers F et al. 1996 A subpopulation of B220+ cells in murine bone marrow does not express CD19 and

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contains natural killer cell progenitors. Journal of Experimental Medicine 183, 187–194. Rosen DB, Bettadapura J, Alsharifi M et al. 2005 Cutting edge: lectinlike transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. Journal of Immunology 175, 7796–7799. Rosen DB, Araki M, Hamerman JA et al. 2004 A Structural basis for the association of DAP12 with mouse, but not human, NKG2D. Journal of Immunology 173, 2470–2478. Rutishauser U, Acheson A, Hall AK et al. 1988 The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science 240, 53–57. Ryan EJ, Marshall AJ, Magaletti D et al. 2002 Dendritic cellassociated lectin-1: a novel dendritic cell-associated, C-type lectin-like molecule enhances T cell secretion of IL-4. Journal of Immunology 169, 5638–5648. Ryan JC, Turck J, Niemi EC et al. 1992 Molecular cloning of the NK1.1 antigen, a member of the NKR-P1 family of natural killer cell activation molecules. Journal of Immunology 149, 1631–1635. Saito S, Nishikawa K, Morii T et al. 1993 Cytokine production by CD16-CD56bright natural killer cells in the human early pregnancy decidua. International Immunology 5, 559–563. Salcedo M, Bousso P, Ljunggren HG et al. 1998 The Qa-1b molecule binds to a large subpopulation of murine NK cells. European Journal of Immunology 28, 4356–4361. Saleh A, Davies GE, Pascal V et al. 2004 Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation. Immunity 21, 55–66. Scalzo AA, Lyons PA, Fitzgerald NA, et al. 1995 The BALB.B6Cmv1r mouse: a strain congenic for Cmv1 and the NK gene complex. Immunogenetics 41, 148–151. Scalzo AA, Fitzgerald NA, Simmons A et al. 1990 Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. Journal of Experimental Medicine 171, 1469–1483. Screpanti V, Wallin RP, Ljunggren HG et al. 2001 A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. Journal of Immunology 167, 2068–2073. Seaman WE, Sleisenger M, Eriksson E et al. 1987 Depletion of natural killer cells in mice by monoclonal antibody to NK-1.1. Reduction in host defense against malignancy without loss of cellular or humoral immunity. Journal of Immunology 138, 4539–4544. Shibuya K, Lanier LL, Phillips JH et al. 1999 Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 11, 615–623. Shinkai Y, Rathbun G, Lam KP et al. 1992 RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867. Shlapatska LM, Mikhalap SV, Berdova AG et al. 2001 CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. Journal of Immunology 166, 5480–5487. Shortman K, Wilson A, Scollay R et al. 1983 Development of large granular lymphocytes with anomalous, non-specific cytotoxicity in clones derived from Ly2+ T cells. Proceedings of the National Academy of Sciences of the USA 80, 2728–2732. Sivori S, Vitale M, Morelli L et al. 1997 p46, a novel natural killer cell-specific surface molecule that mediates cell activation. Journal of Experimental Medicine 186, 1129–1136. Smith HR, Heusel JW, Mehta IK et al. 2002 Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proceedings of the National Academy of Sciences of the USA 99, 8826–8831. Smith HR, Chuang HH, Wang LL et al. 2000 Nonstochastic coexpression of activation receptors on murine natural killer cells. Journal of Experimental Medicine 191, 1341–1354. Smith HRC, Karlhofer FM, Yokoyama WM 1994 Ly-49 multigene family expressed by IL-2-activated NK cells. Journal of Immunology 153, 1068–1079. Smith KM, Wu J, Bakker AB, et al. 1998 Cutting edge: Ly-49D

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Symposium - NK cells and their receptors - WM Yokoyama & JK Riley

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and Ly-49H associate with mouse DAP12 and form activating receptors. Journal of Immunology 161, 7–10. Smyth MJ, Swann J, Cretney E et al. 2005 NKG2D function protects the host from tumor initiation. Journal of Experimental Medicine 202, 583–588. Soderstrom K, Corliss B, Lanier LL et al. 1997 CD94/NKG2 is the predominant inhibitory receptor involved in recognition of HLA-G by decidual and peripheral blood NK cells. Journal of Immunology 159, 1072–1075. Soloski MJ, DeCloux A, Aldrich CJ et al. 1995 Structural and functional characteristics of the class IB molecule, Qa-1. Immunological Reviews 147, 67–89. Starkey PM, Sargent IL, Redman CW 1988 Cell populations in human early pregnancy decidua: characterization and isolation of large granular lymphocytes by flow cytometry. Immunology 65, 129–134. Stern N, Markel G, Arnon TI et al. 2005 Carcinoembryonic antigen (CEA) inhibits NK killing via interaction with CEA-related cell adhesion molecule 1. Journal of Immunology 174, 6692–6701. Stoneman ER, Bennett M, An J et al. 1995 Cloning and characterization of 5E6(Ly-49C), a receptor molecule expressed on a subset of murine natural killer cells. Journal of Experimental Medicine 182, 305–313. Suttles J, Schwarting GA, Stout RD 1986 Flow cytometric analysis reveals the presence of asialo GM1 on the surface membrane of alloimmune cytotoxic T lymphocytes. Journal of Immunology 136, 1586–1591. Tagaya Y, Bamford RN, DeFilippis AP et al. 1996 IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 4, 329–336. Tahara-Hanaoka S, Shibuya K, Onoda Y et al. 2004 Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112). International Immunology 16, 533–538. Takai T, Li M, Sylvestre D et al. 1994 FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell 76, 519–529. Takeda K, Hayakawa Y, Smyth MJ et al. 2001 Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nature Medicine 7, 94–100. Tanaka T, Kitamura F, Nagasaka Y et al. 1993 Selective long-term elimination of natural killer cells in vivo by an anti-interleukin 2 receptor beta chain monoclonal antibody in mice. Journal of Experimental Medicine 178, 1103–1107. Taniguchi T, Minami Y 1993 Minireview: The IL-2/IL-2 receptor system: a current overview. Cell 73, 5–8. Tassi I, Colonna M 2005 The cytotoxicity receptor CRACC (CS-1) recruits EAT-2 and activates the PI3K and phospholipase Cgamma signaling pathways in human NK cells. Journal of Immunology 175, 7996–8002. Timonen T, Ortaldo JR, Herberman RB 1981 Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. Journal of Experimental Medicine 153, 569–582. Tormo J, Natarajan K, Margulies DH et al. 1999 Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 402, 623–631. Tortorella D, Gewurz BE, Furman MH et al. 2000 Viral subversion of the immune system. Annual Review of Immunology 18, 861–926. Tripp CS, Wolf SF, Unanue ER 1993 Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proceedings of the National Academy of Sciences of the USA 90, 3725–3729. Ulbrecht M, Honka T, Person S et al. 1992 The HLA-E gene encodes two differentially regulated transcripts and a cell surface protein. Journal of Immunology 149, 2945–2953. Vacca P, Pietra G, Falco M et al. 2006 Analysis of natural killer cells isolated from human decidua: Evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function. Blood 108, 4078–4085.

Vales-Gomez M, Erskine RA, Deacon MP et al. 2001 The role of zinc in the binding of killer cell Ig-like receptors to class I MHC proteins. Proceedings of the National Academy of Sciences of the USA 98, 1734–1739. Vales-Gomez M, Reyburn HT, Erskine RA et al. 1999 Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. EMBO Journal 18, 4250–4260. Vales-Gomez M, Reyburn HT, Erskine RA et al. 1998a Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. Proceedings of the National Academy of Sciences of the USA 95, 14326–14331. Vales-Gomez M, Reyburn HT, Mandelboim M et al. 1998b Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors. Immunity 9, 337–344. Vance RE, Jamieson AM, Raulet DH 1999 Recognition of the class Ib molecule Qa-1(b) by putative activating receptors CD94/NKG2C and CD94/NKG2E on mouse natural killer cells. Journal of Experimental Medicine 190, 1801–1812. Vance RE, Kraft JR, Altman JD et al. 1998 Mouse CD94/NKG2A is a natural killer cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1(b). Journal of Experimental Medicine 188, 1841–1848. Varki A, Angata T 2006 Siglecs − the major subfamily of I-type lectins. Glycobiology 16, 1R-27R. Veillette A 2006 Immune regulation by SLAM family receptors and SAP-related adaptors. Nature Reviews Immunology 6, 56–66. Verma S, King A, Loke YW 1997 Expression of killer cell inhibitory receptors on human uterine natural killer cells. European Journal of Immunology 27, 979–983. Vitale M, Castriconi R, Parolini S et al. 1999 The leukocyte Ig-like receptor (LIR)-1 for the cytomegalovirus UL18 protein displays a broad specificity for different HLA class I alleles: analysis of LIR1 + NK cell clones. International Immunology 11, 29–35. Vitale M, Bottino C, Sivori S et al. 1998 NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complexrestricted tumor cell lysis. Journal of Experimental Medicine 187, 2065–2072. Wagtmann N, Biassoni R, Cantoni C et al. 1995a Molecular clones of the p58 NK cell receptor reveal immunoglobulin-related molecules with diversity in both the extra- and intracellular domains. Immunity 2, 439–449. Wagtmann N, Rajagopalan S, Winter CC et al. 1995b Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. Immunity 3, 801–809. Wang H, Dey SK 2006 Roadmap to embryo implantation: clues from mouse models. Nature Reviews Genetics 7, 185–199. Wang J, Whitman MC, Natarajan K et al. 2002 Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand. Crucial contacts include both H-2Dd and beta 2-microglobulin. Journal of Biological Chemistry 277, 1433–1442. Ware CF 2005 Network communications: lymphotoxins, LIGHT, and TNF. Annual Review of Immunology 23, 787–819. Wei XH, Orr HT 1990 Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue. Human Immunology 29, 131–142. Weis WI, Drickamer K 1996 Structural basis of lectin–carbohydrate recognition. Annual Review of Biochemistry 65, 441–473. Welch AY, Kasahara M, Spain LM 2003 Identification of the mouse killer immunoglobulin-like receptor-like (Kirl) gene family mapping to chromosome X. Immunogenetics 54, 782–790. Welte SA, Sinzger C, Lutz SZ et al. 2003 Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein. European Journal of Immunology 33, 194–203. Wilhelm BT, Gagnier L, Mager DL 2002 Sequence analysis of the Ly49 cluster in C57BL/6 mice: a rapidly evolving multigene family in the immune system. Genomics 80, 646–661. Willcox BE, Thomas LM, Bjorkman PJ 2003 Crystal structure of

RBMOnline®

Symposium - NK cells and their receptors - WM Yokoyama & JK Riley HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nature Immunology 4, 913–919. Wilson MJ, Torkar M, Haude A et al. 2000 Plasticity in the organization and sequences of human KIR/ILT gene families. Proceedings of the National Academy of Sciences of the USA 97, 4778–4783. Wolan DW, Teyton L, Rudolph MG et al. 2001 Crystal structure of the murine NK cell-activating receptor NKG2D at 1.95 A. Nature Immunology 2, 248–254. Wong S, Freeman JD, Kelleher C et al. 1991 Ly-49 multigene family. New members of a superfamily of type II membrane proteins with lectin-like domains. Journal of Immunology 147, 1417–1423. Wu J, Chalupny NJ, Manley TJ et al. 2003 Intracellular retention of the MHC class I-related chain B ligand of NKG2D by the human cytomegalovirus UL16 glycoprotein. Journal of Immunology 170, 4196–4200. Wu J, Cherwinski H, Spies T et al. 2000 DAP10 and DAP12 form distinct, but functionally co-operative, receptor complexes in natural killer cells. Journal of Experimental Medicine 192, 1059– 1068. Wu J, Song Y, Bakker AB et al. 1999 An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730–732. Xie X, He H, Colonna M et al. 2005 Pathways participating in activation of mouse uterine natural killer cells during pregnancy. Biology of Reproduction 73, 510–518. Yamada H, Shimada S, Morikawa M et al. 2005 Divergence of natural killer cell receptor and related molecule in the decidua from sporadic miscarriage with normal chromosome karyotype. Molecular Human Reproduction 11, 451–457. Yokoyama WM 1997 The mother−child union: the case of missingself and protection of the fetus. Proceedings of the National Academy of Sciences of the USA 94, 5998–6000. Yokoyama WM 1995 Natural killer cells. Right-side-up and up-sidedown NK-cell receptors. Current Biology 5, 982–985. Yokoyama WM 1993 Recognition structures on natural killer cells. Current Opinion in Immunology 5, 67–73.

Yokoyama WM, Seaman WE 1993 The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annual Reviews of Immunology 11, 613–635. Yokoyama WM, Kim S, French AR 2004 The dynamic life of natural killer cells. Annual Review of Immunology 22, 405–429. Yokoyama WM, Ryan JC, Hunter JJ et al. 1991 cDNA cloning of mouse NKR-P1 and genetic linkage with Ly-49. Identification of a natural killer cell gene complex on mouse chromosome 6. Journal of Immunology 147, 3229–3236. Yokoyama WM, Kehn PJ, Cohen DI et al. 1990 Chromosomal location of the Ly-49 (A1, YE1/48) multigene family. Genetic association with the NK 1.1 antigen. Journal of Immunology 145, 2353–2358. Yokoyama WM, Jacobs LB, Kanagawa O et al. 1989 A murine T lymphocyte antigen belongs to a supergene family of type II integral membrane proteins. Journal of Immunology 143, 1379– 1386. Young WW Jr, Hakomori SI, Durdik JM et al. 1980 Identification of ganglio-N-tetraosylceramide as a new cell surface marker for murine natural killer (NK) cells. Journal of Immunology 124, 199–201. Yu YYL, Kumar V, Bennett M 1992 Murine natural killer cells and marrow graft rejection. Annual Review of Immunology 10, 189–213. Zhang JQ, Nicoll G, Jones C et al. 2000 Siglec-9, a novel sialic acid binding member of the immunoglobulin superfamily expressed broadly on human blood leukocytes. Journal of Biological Chemistry 275, 22121–22126. Zhou H, Kartsogiannis V, Hu YS et al. 2001 A novel osteoblastderived C-type lectin that inhibits osteoclast formation. Journal of Biological Chemistry 276, 14916–14923. Received 2 August 2007; refereed 30 August 2007; accepted 14 December 2007.

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